Carboxylic acid compound, method for preparation thereof, and use thereof

ABSTRACT

The present invention relates to the technical field of medicine, and specifically relates to the carboxylic acid compound represented by the chemical formula I or chemical formula II, and a pharmaceutically acceptable salt, a prodrug, and a solvate thereof, and a method for preparation thereof, as well as a pharmaceutical composition containing the described substances, and a use thereof.

TECHNICAL FIELD

The invention relates to pharmaceutical technical field, specifically,to carboxylic acid compounds and pharmaceutically acceptable salts,prodrugs, and solvates thereof and preparation methods thereof, and topharmaceutical compositions comprising the same and uses thereof.

BACKGROUND TECHNIQUE

Uric acid is the final metabolite of diet and purine in human body. Invivo environment (pH 7.4, 37 degrees), uric acid is present in bloodmainly in the form of sodium salt of uric acid, the serum uric acidvalue of normal people is generally lower than 6 mg/dL. When uric acidin serum exceeds 7 mg/dL (Shi, et al., Nature 2003, 425: 516-523),sodium salt of uric acid will crystallize out and precipitate on jointsand other parts of the body, and result in disorders such as gout,urinary stones, kidney stones, etc. Patients with gout are oftenaccompanied with other complications, including hypertension, diabetes,hyperlipidemia, dyslipidemia, atherosclerosis, obesity, metabolicdisease, nephropathy, cardiovascular disease, and respiratory disease,etc. (Rock, Et al., Nature Reviews Rheumatology 2013, 9: 13-23). In2002, Japanese scientists Endou group reported that anion transportchannel protein URAT1 is a major protein responsible for reabsorption ofuric acid in kidney, they also found that the blood uric acid in peoplewith URAT1 gene mutation (causing the synthesis of such protein beinginterrupted, inducing nonfunctional proteins) is only one-tenth of thatin normal people (Enomoto et. al., Nature 2002 417: 447-452). Thesefindings in human genetics demonstrate that URAT1 anion transportprotein in kidney plays very important role in concentration of uricacid in blood, and indicates that URAT1 is a very good and specifictarget of a drug for reducing blood uric acid.

The main objective in the treatment of gout and its complications causedby higher level of blood uric acid is to reduce blood uric acid to lowerthan 6 mg/dL, the main methods are as follows: 1) to inhibit thegeneration of uric acid, such as allopurinol, febuxostat, which aredrugs for inhibiting Xanthine oxidase; 2) to inhibit the reabsorption ofuric acid, such as benzbromarone and probenecid, and lesinurad which iscurrently in clinical research, all of which are drugs for inhibitingkidney URAT1 anion transport channel protein.

In addition to URAT1, there are other cation transport channel proteinsin kidney, such as Glut9 and OAT1 etc., which are also found to be ableto reabsorb uric acid back to blood from renal tubules. Kidney is amajor excretion pathway of uric acid in human body (70%), intestinalsystem (via ABCG2 etc.,) is responsible for excreting approximate 30% ofuric acid (Sakurai, et. al., Current Opinion in Nephology andHypertension 2013, 22: 545-550).

Human urate anion transporter 1, hURAT1, a member of anion transporterfamily, is located at luminal surface side of epithelial cells of renalproximal convoluted tubules, mainly participates in the reabsorption ofuric acid in renal proximal convoluted tubules. URAT1 accomplishesreabsorption of uric acid and excretion of small amount of uric acid byexchanging univalent anions within cells with uric acid in lumens. Aniontransport channel proteins located in renal proximal convoluted tubulesalso comprise anion transport channel protein OAT4, which has 42% ofsimilarity with URAT1 (amino acids of protein). Therefore, generally, apotent URAT1 inhibitor will also inhibit OAT4 and some other aniontransport channel proteins.

At present, all the clinical drugs for reducing blood uric acid havesome side effects, for example, allopurinol will cause life-threateninghypersensitivity in some populations, febuxostat has cardiovascular sideeffects, and benzbromarone has liver toxicity and has been taken back bySanofi from some markets. Therefore, it is urgent to search for novel,efficient and low-toxic drugs for reducing blood uric acid, and thiswill have great clinical significance and application prospects.

Thioacetate compounds have been reported in the prior art, e.g., a classof phenylthioacetate compounds were reported in CN102939279A, a class ofthioacetate compounds were reported in CN103068801A, wherein thioacetatecompounds in CN103068801A are obtained from the compounds inCN102939279A by essentially replacing carbons of benzene groups inskeletons of the compounds in CN102939279A with 1 to 4 N atoms.

Since categories of drugs for gout treatment are very limited in market,it is important to develop anti-gout drugs with high efficiency and lowtoxicity.

CONTENTS OF THE INVENTION

According to one aspect of the present invention, one objective of thepresent invention is to design and synthesize a carboxylic acidcompound, and pharmaceutically acceptable salts, prodrugs, and solvatesthereof.

According to another aspect of the present invention, another objectiveof the present invention is to provide a preparation method of thecarboxylic acid compound, and pharmaceutically acceptable salts,prodrugs, and solvates thereof.

According to another aspect of the present invention, another objectiveof the present invention is to provide a use of the carboxylic acidcompound, and pharmaceutically acceptable salts, prodrugs, and solvatesthereof in the preparation of a drug for promoting the excretion of uricacid with URAT1 as a target.

According to another aspect of the present invention, another objectiveof the present invention is to provide a pharmaceutical compositioncomprising one or more selected from the carboxylic acid compound, andpharmaceutically acceptable salts, prodrugs, and solvates thereof.

The carboxylic acid compound according to the present invention isrepresented by the following Chemical Formula I:

Wherein,

-   -   X is C or N;    -   Y, W and Z are each independently C or N;    -   A is S, N, SO₂, O or absent;    -   Q is substituted or unsubstituted C1-6 straight-chain or        branched-chain alkylene, substituted or unsubstituted C3-6        cycloalkylene, substituted or unsubstituted C6-12 arylene,        wherein substituent is —CD₃, C1-6 alkyl, C3-6 cycloalkyl, C3-6        cycloalkylene or halogen;    -   M is H, Na, K, Ca or C1-4 alkyl;    -   R¹, R² and R³ are each independently hydrogen, halogen or        absent;    -   R^(a) and R^(b) are each independently hydrogen, C1-6 alkyl or        bond to each other to form a substituted or unsubstituted C6-10        aromatic ring structure, wherein the substituent in the        substituted C6-10 aromatic ring structure is halogen, C1-3 alkyl        or C1-3 alkoxy;    -   R^(c) is —CN, carboxyl, hydroxyl-substituted or unsubstituted        C1-6 alkyl, hydroxyl-substituted or unsubstituted C3-6        cycloalkyl, hydroxyl-substituted or unsubstituted 3- to        6-membered heterocycloalkyl containing 1 to 3 heteroatoms        selected from O, S and N.

Preferably,

-   -   X is C or N;    -   Y, W and Z are each independently C or N;    -   A is S, N, SO₂, O or absent;    -   Q is substituted or unsubstituted C1-3 straight-chain or        branched-chain alkylene, substituted or unsubstituted C3-5        cycloalkylene, phenyl, wherein substituent is —CD₃, C1-3 alkyl,        C3-5 cycloalkyl, C3-5 cycloalkylene or halogen selected from        fluorine, chlorine, bromine and iodine;    -   M is H, Na, K, Ca or C1-4 alkyl;    -   R¹, R² and R³ are each independently hydrogen, halogen or        absent;    -   R^(a) and R^(b) are each independently hydrogen, C1-3 alkyl or        bond to each other to form a substituted or unsubstituted        benzene ring structure, wherein the substituent in the        substituted benzene ring structure is halogen, C1-3 alkyl or        C1-3 alkoxy;    -   R^(c) is —CN, carboxyl, hydroxyl-substituted or unsubstituted        C1-3 alkyl, hydroxyl-substituted or unsubstituted C3-5        cycloalkyl, hydroxyl-substituted or unsubstituted 3- to        5-membered heterocycloalkyl containing 1 to 3 heteroatoms        selected from O, S and N.

More preferably,

-   -   X is C or N;    -   Y, W and Z are each independently C or N;    -   A is S, N, SO₂, O or absent;    -   Q is substituted or unsubstituted C1-3 straight-chain or        branched-chain alkylene,

phenyl, wherein substituent is methyl, ethyl, propyl, —CD₃, C3-5cycloalkyl, C3-5 cycloalkylene or fluorine;

-   -   M is H;    -   R¹, R² and R³ are each independently hydrogen, halogen or        absent;    -   R^(a) and R^(b) are each independently hydrogen, or bond to each        other to form a benzene ring;    -   R^(c) is —CN, carboxyl, methyl, ethyl, propyl, hydroxymethyl,        hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl,        hydroxyl-substituted cyclopropyl, hydroxyl-substituted        cyclobutyl, oxiranyl, oxetanyl, hydroxyl-substituted oxiranyl or        hydroxyl-substituted oxetanyl.

Further preferably,

-   -   X is C or N;    -   Y, W and Z are each independently C or N;    -   A is S;    -   Q is substituted or unsubstituted ethylene, propylene,        isopropylidene,

phenyl, wherein substituent is methyl, ethyl, propyl, —CD₃, cyclopropyl,cyclobutyl, cyclopentyl, cyclopropylidene, cyclobutylidene,cyclopentylidene or fluorine;

-   -   M is H;    -   R¹, R² and R³ are each independently hydrogen, halogen or        absent;    -   R^(a) and R^(b) are each independently hydrogen, or bond to each        other to form a benzene ring;    -   R^(c) is —CN, carboxyl, methyl, ethyl, propyl, hydroxymethyl,        hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl,        hydroxyl-substituted cyclopropyl, hydroxyl-substituted        cyclobutyl, oxiranyl, oxetanyl, hydroxyl-substituted oxiranyl or        hydroxyl-substituted oxetanyl.

In one embodiment, the carboxylic acid compound according to the presentinvention is represented by the following chemical formula II:

Wherein,

-   -   X is C or N;    -   Y, W and Z are each independently C or N;    -   A is S, N, SO₂, O or absent;    -   Q is substituted or unsubstituted C1-6 straight-chain or        branched-chain alkylene, substituted or unsubstituted C3-6        cycloalkylene, substituted or unsubstituted C6-12 arylene,        wherein substituent is —CD₃, C1-6 alkyl, C3-6 cycloalkyl, C3-6        cycloalkylene or halogen;    -   M is H, Na, K, Ca or C1-4 alkyl;    -   R¹, R² and R³ are each independently hydrogen, halogen or        absent;    -   R^(a) and R^(b) are each independently hydrogen, C1-6 alkyl or        bond to each other to form a substituted or unsubstituted C6-10        aromatic ring structure, wherein the substituent in the        substituted C6-10 aromatic ring structure is halogen, C1-3 alkyl        or C1-3 alkoxy;    -   R^(c) is —CN, carboxyl, hydroxyl-substituted or unsubstituted        C1-6 alkyl, hydroxyl-substituted or unsubstituted C3-6        cycloalkyl, hydroxyl-substituted or unsubstituted 3- to        6-membered heterocycloalkyl containing 1 to 3 heteroatoms        selected from O, S and N.

Preferably,

-   -   X is C or N;    -   Y, W and Z are each independently C or N;    -   A is S, N, SO₂, O or absent;    -   Q is substituted or unsubstituted C1-3 straight-chain or        branched-chain alkylene, substituted or unsubstituted C3-5        cycloalkylene, phenyl, wherein substituent is —CD₃, C1-3 alkyl,        C3-5 cycloalkyl, C3-5 cycloalkylene or halogen selected from        fluorine, chlorine, bromine and iodine;    -   M is H, Na, K, Ca or C1-4 alkyl;    -   R¹, R² and R³ are each independently hydrogen, halogen or        absent;    -   R^(a) and R^(b) are each independently hydrogen, C1-3 alkyl or        bond to each other to form a substituted or unsubstituted        benzene ring structure, wherein the substituent in the        substituted benzene ring structure is halogen, C1-3 alkyl or        C1-3 alkoxy;    -   R^(c) is —CN, carboxyl, hydroxyl-substituted or unsubstituted        C1-3 alkyl, hydroxyl-substituted or unsubstituted C3-5        cycloalkyl, hydroxyl-substituted or unsubstituted 3- to        5-membered heterocycloalkyl containing 1 to 3 heteroatoms        selected from O, S and N.

More preferably,

-   -   X is C or N;    -   Y, W and Z are each independently C or N;    -   A is S, N, SO₂, O or absent;    -   Q is substituted or unsubstituted C1-3 straight-chain or        branched-chain alkylene,

phenyl, wherein substituent is methyl, ethyl, propyl, —CD₃, C3-5cycloalkyl, C3-5 cycloalkylene or fluorine;

-   -   M is H;    -   R¹, R² and R³ are each independently hydrogen, halogen or        absent;    -   R^(a) and R^(b) are each independently hydrogen, or bond to each        other to form a benzene ring;    -   R^(c) is —CN, carboxyl, methyl, ethyl, propyl, hydroxymethyl,        hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl,        hydroxyl-substituted cyclopropyl, hydroxyl-substituted        cyclobutyl, oxiranyl, oxetanyl, hydroxyl-substituted oxiranyl or        hydroxyl-substituted oxetanyl.

Further preferably,

-   -   X is C or N;    -   Y, W and Z are each independently C or N;    -   A is S;    -   Q is substituted or unsubstituted ethylene, propylene,        isopropylidene,

phenyl, wherein substituent is methyl, ethyl, propyl, —CD₃, cyclopropyl,cyclobutyl, cyclopentyl, cyclopropylidene, cyclobutylidene,cyclopentylidene or fluorine;

-   -   M is H;    -   R¹, R² and R³ are each independently hydrogen, halogen or        absent;    -   R^(a) and R^(b) are each independently hydrogen, or bond to each        other to form a benzene ring;    -   R^(c) is —CN, carboxyl, methyl, ethyl, propyl, hydroxymethyl,        hydroxyethyl, hydroxypropyl, cyclopropyl, cyclobutyl,        hydroxyl-substituted cyclopropyl, hydroxyl-substituted        cyclobutyl, oxiranyl, oxetanyl, hydroxyl-substituted oxiranyl or        hydroxyl-substituted oxetanyl.

According to another embodiment of the present invention, the carboxylicacid compound according to the present invention is selected from thefollowing specific compounds 1 to 41:

In the present invention, the pharmaceutically acceptable salts of thecompounds in the present invention are not particularly limited, as longas they are pharmaceutically acceptable, examples include, but are notlimited to, ammonium salts, alkali metal salts and alkaline-earth metalsalts, such as ammonium salts, sodium salts, potassium salts, calciumsalts and the like.

The present invention also includes isotopically-labeled compounds ofthe present invention, these isotopically-labeled compounds areidentical to those recited herein, except that one or more atoms have anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, fluorine and chloride, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N,¹⁸O, ¹⁷O, ¹⁸F and ³⁶Cl.

Certain isotopically-labeled compounds of the present invention (forexample, compounds labeled with ³H and ¹⁴C) can be used in compoundsand/or substrate tissue distribution assays. Tritiated (i.e., ³H) andcarbon-14 (i.e., ¹⁴C) isotopes are particularly preferred for their easeof preparation and detection. Further, substitution with heavy isotopessuch as deuterium (i.e., ²H) may produce certain therapeutic advantagesresulting from greater metabolic stability (for example, extension ofhalf-life in vivo or reduction of dose requirements), and thus beingpreferably used in certain conditions. The isotopically-labeledcompounds of the present invention may generally be prepared byreplacing non-isotope labeled agents with isotopically-labeled agents,by following the procedures similar to those disclosed in the flowroutes and/or examples below.

In the present invention, the prodrugs of the compounds of the presentinvention are not particularly limited, as long as they can bemetabolized in vivo into the compounds of the present invention,examples include, but are not limited to, esters etc., such as methylester, ethyl ester and the like.

Further objective of the present invention is to provide a preparationprocess of the carboxylic acid compound, and pharmaceutically acceptablesalts, prodrugs, and solvates thereof, the process comprises:

Step 1: The starting reactant 1-1 is dissolved in dioxane, thenpotassium acetate, bis(pinacolato)diboron (B₂(pin)₂) and palladiumcatalyst [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium areadded thereto, the mixture is heated and reacted until the reaction iscompleted. The reaction solution is cooled, quenched by addition of icewater, extracted with ethyl acetate, then the organic phase is combinedand washed with saturated brine. The organic phase is dried over sodiumsulfate, then rotatory evaporated and purified by column chromatography,to give compound (1-2).

Step 2: 3-bromo-4-chloropyridine or 2-bromo-1-chlorobenzene is dissolvedin dimethyl formamide and water, compound (1-2) obtained in step 1,sodium carbonate, palladium catalyst [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium are added thereto, then the resultingmixture is heated and reacted. The reaction solution is cooled, quenchedin ice water, extracted with ethyl acetate, washed with saturated brine,and dried over anhydrous sodium sulfate, then rotatory evaporated andpurified by column chromatography, to give compound (1-3).

Step 3: To compound (1-3) obtained in step 2 dissolved in dimethylformamide, is added sodium sulfide, the resulting mixture is heated andreacted, then cooled down to room temperature, after that, anhydrouspotassium carbonate and a reactant

(which is determined by the structure of the final products) are addedthereto, the reaction is carried out at higher temperature until thereaction is completed. The reaction solution is cooled, quenched in icewater and extracted with ethyl acetate, then the organic phase is driedover anhydrous sodium sulfate, filtered and rotatory evaporated, to givecompound (1-4). The crude product is directly subject to the next step.

Step 4: The reaction is carried out overnight between compound (1-4)obtained in step 3 and lithium hydroxide in tetrahydrofuran and water atroom temperature. Tetrahydrofuran is removed by concentration, andaqueous phase is extracted with dichloromethane and collected. Aqueousphase is then adjusted to pH 4-5 using 2N of hydrochloric acidregulating system, and extracted with dichloromethane. The organic phaseis combined, dried and rotatory evaporated, to give the final compoundof chemical formula (1-5).

The reaction is carried out overnight between compound (1-3) and areactant

(which is determined by the structure of the final product) in phenol athigher temperature. Then, the reaction solution is cooled down to roomtemperature, added with ether and filtered. The filter cake is purifiedby preparative reverse phase chromatography to give the final product(2-1).

Step 1: A reactant

which is determined by the structure of final product,triphenylphosphine and diethyl azodicarboxylate are sequentially addedto 3-bromopyridin-4-ol or 2-bromophenol (3-1) dissolved intetrahydrofuran under the protection of nitrogen at 0° C., then themixture is warmed to room temperature and reacted. The reaction solutionis directly concentrated and then purified by preparative silica gelplate to give compound (3-2).

Step 2: The resulting compound (3-2), aqueous solution of sodiumcarbonate, compound (1-2) and tetrakis(triphenylphosphine) palladium(0)are added to dioxane, heated to 80° C. and reacted for 12 hours. Thenthe reaction solution is cooled down to room temperature, the reactionsolution is added with ethyl acetate, and washed with water and brine.The organic phase is dried, filtered, concentrated and purified bypreparative silica gel plate, to give compound (3-3).

Step 3: Compound (3-3), lithium hydroxide or sodium hydroxide are addedto tetrahydrofuran/water, and the mixture was reacted at roomtemperature for hours. Then the pH of the reaction solution is adjustedwith concentrated hydrochloric acid, and the reaction solution is addedwith ethyl acetate, washed with water and brine. The organic phase isdried, filtered, concentrated and purified by preparative silica gelplate, to give compound (3-4).

Step 1: The starting reactant 4-1 is dissolved in dioxane, thenpotassium acetate, bis(pinacolato)diboron (B₂(pin)₂) and palladiumcatalyst [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium areadded thereto, then the mixture is heated and reacted until the reactionis completed. The reaction solution is cooled, quenched by addition ofice water and extracted with ethyl acetate, then the organic phase iscombined and washed with saturated brine. The organic phase is driedover sodium sulfate, then rotatory evaporated and purified by columnchromatography, to give compound (4-2).

Step 2: 3-bromo-4-chloropyridine or 2-bromo-1-chlorobenzene is dissolvedin dimethyl formamide and water, compound (4-2) obtained in step 1,sodium carbonate, palladium catalyst[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium are addedthereto at the same time, then the resulting mixture is heated andreacted. The reaction solution is cooled, quenched in ice water,extracted with ethyl acetate, washed with saturated brine, dried oversodium sulfate, then rotatory evaporated and purified by columnchromatography, to give compound (4-3).

Step 3: To compound (4-3) obtained in step 2 dissolved in dimethylformamide, is added sodium sulfide, the resulting mixture is heated andreacted, then cooled down to room temperature, after that, anhydrouspotassium carbonate and a reactant

(which is determined by the structure of the final product) are addedthereto, and the reaction is carried out at higher temperature until thereaction is completed. The reaction solution is cooled, quenched in icewater and extracted with ethyl acetate, then the organic phase is driedover sodium sulfate, filtered and rotatory evaporated, to give compound(4-4). The crude product is directly subject to the next step.

Step 4: The reaction is carried out overnight between compound (4-4)obtained in step 3 and lithium hydroxide in tetrahydrofuran and water atroom temperature. Tetrahydrofuran is removed by concentration, andaqueous phase is extracted with dichloromethane and collected. Then theaqueous phase is adjusted to pH 4-5 using 2N of hydrochloric acidregulating system, and extracted with dichloromethane. The organic phaseis combined, dried, then rotatory evaporated, to give the final compoundof chemical formula (4-5).

Step 1: 3-bromo-4-methylpyridine is dissolved in tetrahydrofuran, thesolution is cooled and then lithium diisopropylamide (LDA) is addedthereto and reacted, then the reactant

which is determined by the structure of the final product, is addeddropwise thereto and the reaction is continued. Thereafter, the reactionis quenched with saturated sodium bicarbonate solution, and then thereaction solution is added with ethyl acetate, washed with water andbrine. The organic phase is dried, filtered, concentrated and purifiedby preparative silica gel plate, to give compound (5-1).

Step 2: Compound (5-1), aqueous solution of sodium carbonate, compound(1-2), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium are addedto dimethyl formamide, heated until they reacted. The reaction solutionis added with ethyl acetate, washed with water and brine. The organicphase is dried, filtered, concentrated and purified by preparativesilica gel plate, to give compound (5-2).

Step 3: Compound (5-2) and lithium hydroxide are added totetrahydrofuran/water and reacted at room temperature. The pH ofreaction solution is adjusted with dilute hydrochloric acid (1 M), andthen the reaction solution is added with ethyl acetate, washed withwater and brine. The organic phase is dried, filtered, concentrated andpurified by preparative silica gel plate, to give compound (5-3).

Step 1: Compound (1-3), anhydrous potassium carbonate and reactant

are added to dimethyl formamide, stirred at room temperature, thenstirred at higher temperature. The mixture is then cooled to roomtemperature, added with water and ethyl acetate, after that, the organiclayer is washed with saturated brine, dried over sodium sulfate, and thesolvent is distilled off under reduced pressure, to obtain a crude brownoil which is purified by column chromatography to yield compound (6-1-1)and compound (6-2-1) respectively.

Step 2: Compound (6-1-1) and compound (6-2-1) are dissolved intetrahydrofuran respectively, and are slowly added by dropwise tosuspension of sodium hydride in dimethyl formamide at 0° C. whilestirring, a solution of Iodomethane-d3 in dimethyl formamide is furtheradded thereto at 0° C., then the resulting mixture is stirred overnightat room temperature. The reaction is quenched by addition water, its pHis adjusted with 1 N hydrochloric acid, then the solvent is distilledoff under reduced pressure, and the remaining oily substance is purifiedby preparative HPLC, to give compound (6-1-2) and compound (6-2-2)respectively.

Step 3: Compound (6-1-2) and lithium hydroxide are added totetrahydrofuran/water (3 mL/1 mL), and reacted at room temperature. Thereaction solution is adjusted to pH 4 with dilute hydrochloric acid (1M), then the reaction solution is added with ethyl acetate and washedwith brine. The organic phase is dried, filtered, concentrated andpreparatively purified, to give compound (6-1-3).

According to another aspect of the invention, further provided herein isa use of the carboxylic acid compound, and pharmaceutically acceptablesalts, prodrugs, and solvates thereof in the preparation of a drug thatpromotes the excretion of uric acid, preferably, a drug that promotesthe excretion of uric acid with URAT1 as a target.

According to another aspect of the invention, further provided herein isa pharmaceutical composition comprising one or more selected from thecarboxylic acid compound, and pharmaceutically acceptable salts,prodrugs, and solvates thereof, and optionally a pharmaceuticallyacceptable carrier.

According to another aspect of the invention, further provided herein isa use of the carboxylic acid compound, and pharmaceutically acceptablesalts, prodrugs, and solvates thereof or pharmaceutical compositionthereof in the preparation of a drug for the treatment or prevention ofa disease or disorder caused by abnormal organ or tissue levels of uricacid in an individual.

Wherein, the disease or disorder caused by abnormal organ or tissuelevels of uric acid in an individual includes: gout, gouty arthritis, arecurrent gout attack, hyperuricemia, joint inflammation, arthritis,urolithiasis, kidney disease, kidney stones, kidney failure,hypertension, cardiovascular disease, coronary heart disease,Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, plumbism,hyperparathyroidism, psoriasis and sarcoidosis.

Preferably, the disease or disorder is hyperuricemia in human andanimals, or gout in human and animals.

According to another aspect of the invention, further provided herein isa use of the carboxylic acid compound, and pharmaceutically acceptablesalts, prodrugs, and solvates thereof or the pharmaceutical compositionthereof in the preparation of a drug for lowering blood levels of uricacid in human and animals.

According to another aspect of the invention, a use of the carboxylicacid compound, and pharmaceutically acceptable salts, prodrugs, andsolvates thereof or the pharmaceutical composition thereof in thepreparation of a drug for lowering blood levels of uric acid in humanand animals.

Further provided herein is a combination of the carboxylic acidcompound, and pharmaceutically acceptable salts, prodrugs, and solvatesthereof or a pharmaceutical composition thereof with a second agenteffective for the treatment of gout.

Wherein, the second agent is a xanthine oxidase inhibitor, a xanthinedehydrogenase inhibitor, a xanthine oxidoreductase inhibitor, or acombination thereof, preferably, allopurinol, febuxostat or acombination thereof.

The pharmaceutical composition or drugs provided herein can be invarious forms, such as tablet, capsule, powder, syrup, solution,suspension and aerosol, etc., and can be present in suitable solid orliquid carriers or diluents and in disinfected instruments suitable forinjection or infusion.

Various formulations of the pharmaceutical compositions or drugs of thepresent invention can be prepared according to conventional preparationprocesses in the pharmaceutical field. Unit dosage of these formulationscontains 0.05 mg-200 mg compounds of formula (I) or (II), preferably,unit dosage of these formulations contains 0.1 mg-100 mg compounds offormula (I) or (II).

The compounds and pharmaceutical compositions of the present inventioncan be clinically used for mammals, including human and animals, and canbe administered via oral, nasal, dermal, pulmonary, or gastrointestinaletc. administration routes, Oral route is the most preferable. Theoptimal preferred daily dosage is 0.001-10 mg/kg body weight,administered at one time, or 0.001-10 mg/kg body weight administered atdivided doses. No matter what kinds of administration manners, theoptimal dosage for an individual should be determined by specifictreatment. Generally, the most suitable dosage can be obtained bygradually increasing dosages from a smaller dosage.

In the present invention, term “effective amount” may refer to aneffective amount for dose and period of time required to achievepredicted effects. The effective amount may vary due to some factors,such as categories of diseases or syndromes of diseases duringtreatment, construction of a specific targeted organ being administered,body size of a patient or severity of diseases or syndromes. Withoutexcessive experiments, those with common knowledge in the art candetermine an effective amount for a specific compound by experience.

Technical Effects

The research on anti-uric acid activity demonstrates that the compoundsof the present invention have superior activities in inhibiting thereabsorption of uric acid, and can be used as novel drugs forefficiently decreasing blood uric acid level, especially as URAT1inhibitors.

SPECIFIC EMBODIMENTS

The present invention will be explained with reference to the specificexamples below. It should be understood that, these examples are merelyused for illustrating the present invention but not for limiting thescope of the invention. The experimental methods in the followingexamples, when detailed conditions are not specified, are carried outaccording to conventional conditions, or according to conditionsprovided or constructed by manufacturers. Unless defined or illustratedotherwise, all professional and scientific terms used herein have thesame meaning as commonly known by a person skilled in the art.Additionally, any methods and materials similar or equivalent to therecorded contents can be used in the methods of the present invention.

In the synthetic processes of the following examples, starting materialswere obtained from commercial sources, such as from Alfa Aesar (China)Chem Co. Ltd., Accela ChemBio Co. Ltd, PharmaBlock Sciences (Nanjing),Inc., Dalian Ally Chem Co. Ltd., Tianjin Fuchen chemical reagentfactory, Beijing Jingqiu chemical product Co. Ltd., Zhangjiagang AimateChem Co. Ltd, Sinopharm chemical reagent Shaanxi Co., Ltd, etc.

EXAMPLES Example 1: Synthesis of Compound 1

Step 1: Synthesis of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1-naphthonitrile (1-a)

In a three-necked flask (100 mL), potassium acetate (3.9 g, 39.8 mmol),bis(pinacolato)diboron (B₂(pin)₂) (4.0 g, 15.75 mmol) and palladiumcatalyst [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.54g, 0.66 mmol) were added to 4-bromo-1-naphthonitrile (3.0 g, 15.75 mmol)solution in dioxane (40 mL) under the protection of N₂, the mixture washeated to 90° C. and reacted for 3 hours until the reaction wascompleted. The reaction solution was cooled, quenched by addition of 100mL ice water and extracted with ethyl acetate (100 mL, 3 times), thenthe organic phase was combined and washed with saturated brine (100 mL,3 times). The organic phase was dried over sodium sulfate, then rotatoryevaporated and purified by column chromatography (petroleum ether/ethylacetate=20:110:1), to give an off-white solid product4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1-naphthonitrile (1-a).

Step 2: Synthesis of 4-(4-chloropyridin-3-yl)-1-naphthonitrile (1-b)

In a three-necked flask (100 mL),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1-naphthonitrile (2.4g, 8.6 mmol) obtained in step 1, sodium carbonate (2.8 g, 26.42 mmol),palladium catalyst[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.35 g, 0.43mmol) were added at the same time to 3-bromo-4-chloropyridine (1.6 g,8.31 mmol) solution in dimethyl formamide (40 mL) and water (4.8 mL)under the protection of N₂, then the mixture was heated to 130° C. andreacted for 5 hours. The reaction solution was cooled, quenched byaddition of 100 mL ice water, extracted with ethyl acetate (100 mL, 3times), washed with saturated brine (100 mL, 3 times) and dried oversodium sulfate, then rotatory evaporated and purified by columnchromatography (petroleum ether/ethyl acetate=10:1˜petroleum ether/ethylacetate/dichloromethane=1:1:1), to give an off-white solid product4-(4-chloropyridin-3-yl)-1-naphthonitrile (1-b).

Step 3: Synthesis of methyl1-(((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)methyl)cyclopropanecarboxylate(1-c)

In a three-necked flask (100 mL), under the protection of N₂,4-(4-chloropyridin-3-yl)-1-naphthonitrile (200 mg, 0.70 mmol) obtainedin step 2 was dissolved in dimethyl formamide (20 mL), sodium sulfide(355 mg, 4.50 mmol) was added thereto, then the mixture was heated to130° C. and reacted for about 1 hour, after being cooled down to roomtemperature, anhydrous potassium carbonate (523 mg, 3.70 mmol) andmethyl 1-(bromomethyl)cyclopropanecarboxylate (440 mg, 2.20 mmol) aresequentially added thereto, and then the resulting mixture was heated to130° C. and further reacted for about 1.1 hour until the reaction wascompleted. The reaction solution was cooled, added with 100 mL ice waterto quench the reaction and extracted with ethyl acetate (100 mL, 3times), then the organic phase was dried over anhydrous sodium sulfate,filtered and rotatory evaporated, to give 450 mg of yellow oily productmethyl1-(((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)methyl)cyclopropanecarboxylate(1-c). The crude product was directly subject to the next step.

Step 4: Synthesis of1-(((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)methyl)cyclopropanecarboxylicacid (compound 1)

Methyl1-(((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)methyl)cyclopropanecarboxylate(450 mg, 1.20 mmol) obtained in step 3, lithium hydroxide (90 mg, 3.70mmol), tetrahydrofuran (30 mL) and water (10 mL) were added into athree-necked flask (100 mL) under the protection of N₂, and the mixturewas reacted overnight at room temperature. The resulting mixture wasconcentrated to remove tetrahydrofuran, aqueous phase was extracted 3times with dichloromethane (50 mL), and the aqueous phase was collected.The aqueous phase was adjusted to pH=4-5 with 2N of hydrochloric acidregulating system, and then extracted with dichloromethane (100 mL, 3times). The organic phase was combined, dried with sodium sulfate, andthen rotatory evaporated. The crude product was prepared by highpressure to yield compound 1, a white solid product.

LC-MS (ES, m/z): 361 [M+H]⁺. H-NMR (300 MHz, d₆-DMSO, ppm): δ 0.86-0.94(m, 2H), 1.08-1.14 (m, 2H), 3.38 (s, 2H), 7.54-7.57 (d, J=8.1 Hz, 1H),7.65-7.91 (m, 4H), 8.23-8.26 (d, J=8.4 Hz, 1H), 8.31-8.33 (d, J=7.5 Hz,1H), 8.49 (s, 1H), 8.69-8.71 (d, J=6 Hz, 1H).

Example 2: Synthesis of Compound 2

Compound 2 was synthesized by a method similar to that in Example 1,except that methyl 1-(bromomethyl)cyclopropanecarboxylate was replacedwith the corresponding compound in step 3.

LC-MS (ES, m/z): 335 [M+H]⁺. H-NMR (300 MHz, CD₃OD, ppm): δ2.61-2.65 (m,2H), 3.23-3.28 (m, 2H), 7.53-7.66 (m, 4H), 7.78-7.83 (m, 1H), 8.11-8.13(d, J=7.2 Hz, 1H), 8.29-8.32 (d, J=8.4 Hz, 2H), 8.56 (m, 1H).

Example 3: Synthesis of Compound 3

Compound 3 was synthesized by a method similar to that in Example 1,except that methyl 1-(bromomethyl)cyclopropanecarboxylate was replacedwith the corresponding compound in step 3.

LC-MS (ES, m/z): 349 [M+H]⁺. H-NMR (300 MHz, CDCl₃, ppm): δ1.69-1.79 (m,2H), 2.24-2.29 (m, 2H), 2.95-3.00 (m, 2H), 7.47-7.50 (d, J=8.4 Hz, 1H),7.57-7.70 (m, 3H), 7.82-7.88 (m, 1H), 8.12-8.31 (m, 3H), 8.58-8.60 (d,J=5.4 Hz, 1H), 12.15 (br, 1H).

Example 4: Synthesis of Compound 18

Step 1: Synthesis of 2,2-dimethylthiirane (18-a)

Potassium thiocyanate (9.7 g, 0.1 mol) was dissolved in water (10 mL),and 2,2-dimethyloxirane (7.2 g, 0.1 mol) was added thereto at roomtemperature. After the mixture was reacted for 4 hours, the supernatantwas added dropwise to the aqueous solution (5 mL) of potassiumthiocyanate (5 g, 0.05 mol), and the reaction was lasted for another 16hours. The reaction solution was added with ether (50 mL) and water (30mL), and the organic phase was further washed with brine (10 mL). Thenthe organic phase was dried, filtered and concentrated to yield a yellowoily product.

Step 2: Synthesis of 4-mercapto-4-methylpentanenitrile (18-b)

In a three-necked flask (100 mL), n-butyllithium (2.5 M in hexane, 3.6mL, 9 mmol) was dissolved in tetrahydrofuran (10 mL) under theprotection of nitrogen, the solution was cooled to −78° C., thenacetonitrile (378 mg, 9 mmol) was added thereto, the mixture was reactedfor 0.5 hour, to which was further added dropwise a solution of 18-a(800 mg, 9 mmol) in tetrahydrofuran (20 mL), the resulting mixture washeated to room temperature and reacted for another 4 hours. The reactionwas quenched with 1 N hydrochloric acid (9 mL) at 0° C., then thereaction solution was added with ethyl acetate (50 mL), then washed withbrine (10 mL). The organic phase was dried, filtered and concentrated toyield a yellow oily product.

Step 3: Synthesis of4-(4-((4-cyano-2-methylbutan-2-yl)thio)pyridin-3-yl)-1-naphthonitrile(18-c)

In a single-necked flask (100 mL), 18-b (600 mg, 4.65 mmol), anhydrouspotassium carbonate (641 mg, 4.65 mmol) and 1-b (300 mg, 1.13 mmol) wereadded to dimethyl formamide (15 mL), the mixture was heated to 130° C.and reacted for 2 hours. The reaction solution was cooled, added withethyl acetate (50 mL), washed with water (30 mL) and brine (30 mL). Theorganic phase was dried, filtered, concentrated, and purified by silicagel column (petroleum ether/ethyl acetate=1:1) to yield a white solid.

Step 4: Synthesis of4-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)-4-methylpentanoic acid(18)

18-c (190 mg, 0.53 mmol) and 1 M of aqueous solution of sodium hydroxide(2.1 mL, 2.1 mmol,) were added to tetrahydrofuran/methanol (2 mL/8 mL)in a single-necked flask (50 mL), and the mixture was reacted at 65° C.for 36 hours. The reaction solution was concentrated, adjusted to pH=4with 1N hydrochloric acid, then it was added with ethyl acetate (50 mL)and washed with brine (50 mL). The organic phase was dried, filtered,concentrated and purified by preparative reverse phase chromatography toyield a white solid product.

LC-MS (ES, m/z): 377 [M+H]⁺; H-NMR (400 MHz, DMSO-d6, ppm): δ 12.00 (s,1H), 8.62 (d, J=5.2 Hz, 1H), 8.44 (s, 1H), 8.18-8.23 (m, 2H), 7.81 (m,1H), 7.72 (d, J=5.2 Hz, 1H), 7.65 (m, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.39(d, J=8.4 Hz, 1H), 2.02 (m, 2H), 1.72 (m, 1.13 (s, 6H).

Example 5: Synthesis of Compound 4

Step 1: Synthesis of methyl2-1-(((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)methyl)cyclopropyl)acetate(4-a)

In a three-necked flask (100 mL), under the protection of N₂, anhydrouspotassium carbonate (523 mg, 3.70 mmol) and methyl2-(1-(mercaptomethyl)cyclopropyl)acetate (300 mg, 1.90 mmol) weresequentially added to 4-(4-chloropyridin-3-yl)-1-naphthonitrile (200 mg,0.70 mmol) solution in dimethyl formamide (20 mL), the mixture washeated to 130° C. and reacted for about 2 hour until the reaction wascompleted. The reaction solution was cooled, added with 100 mL ice waterto quench the reaction, and extracted with ethyl acetate (100 mL, 3times), then organic phase was reversely washed with saturated brine(100 mL, 4 times). The organic phase was dried over anhydrous sodiumsulfate, and then rotatory evaporated to yield a yellow oily product.The crude product was directly subject to the next step.

Step 2: Synthesis of2-(1-(((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)methyl)cyclopropyl)aceticacid (compound 4)

Methyl2-(1-(((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)methyl)cyclopropyl)acetate(417 mg, 1.07 mmol) obtained in step 1, lithium hydroxide (78 mg, 3.26mmol), tetrahydrofuran (30 mL) and water (10 mL) were added into athree-necked flask (100 mL) under the protection of N₂, and the mixturewas reacted overnight at room temperature. Then, the resulting solutionwas concentrated to remove tetrahydrofuran, aqueous phase was extracted3 times with dichloromethane (50 mL), and the aqueous phase wascollected. After that, the aqueous phase was adjusted to pH=4-5 with 2Nof hydrochloric acid regulating system, and then extracted withdichloromethane (100 mL, 3 times). The organic phase was combined, driedover sodium sulfate, rotatory evaporated, prepared by high pressure, andthen rotatory evaporated. The resultant was lyophilized to yield a whitesolid.

LC-MS (ES, m/z): 375 [M+H]⁺. H-NMR (300 MHz, CDCl₃, ppm): δ 0.43 (m,4H), 2.06-2.18 (m, 2H), 3.13-3.22 (m, 2H), 7.48-7.70 (m, 4H), 7.83-7.88(m, 1H), 8.22-8.30 (m, 3H), 8.54-8.56 (d, J=5.4 Hz, 1H), 12.23 (br, 1H).

Example 6: Synthesis of Compound 5

Compound 5 was synthesized by a method similar to that in Example 5,except that methyl 2-(1-(mercaptomethyl)cyclopropyl)acetate was replacedwith the corresponding compound in step 1.

LC-MS (ES, m/z): 375 [M+H]⁺. H-NMR (300 MHz, CDCl₃, ppm): δ 1.92-2.01(m, 2H), 2.34-2.47 (m, 3H), 2.97-3.03 (m, 3H), 7.37-59 (m, 3H),7.72-7.77 (t, J=7.8 Hz, 1H), 7.99-8.01 (d, J=7.2 Hz, 1H), 8.33-8.36 (d,J=8.4 Hz, 1H), 8.57-8.59 (d, J=5.4 Hz, 2H), 8.61-8.66 (m, 1H).

Example 7: Synthesis of Compound 6

Compound 6 was synthesized by a method similar to that in Example 5,except that methyl 2-(1-(mercaptomethyl)cyclopropyl)acetate was replacedwith the corresponding compound in step 1.

LC-MS (ES, m/z): 375 [M+H]⁺. H-NMR (300 MHz, CDCl₃, ppm): δ 1.92-2.01(m, 2H), 2.36-2.2.44 (m, 2H), 2.65-2.70 (m, 1H), 2.99-3.09 (m, 3H),7.30-7.59 (m, 4H), 7.71-7.77 (m, 1H), 7.99-8.01 (d, J=7.2 Hz, 1H),8.33-8.34 (m, 2H), 8.58-8.60 (m, 1H).

Example 8: Synthesis of Compound 12

Compound 12 was synthesized by a method similar to that in Example 5,except that methyl 2-(1-(mercaptomethyl)cyclopropyl)acetate was replacedwith the corresponding compound in step 1.

LC-MS (ES, m/z): 385 [M+H]⁺. H-NMR (400 MHz, d₆-DMSO, ppm): δ 8.60 (d,J=6.4 Hz, 1H), 8.31 (s, 1H), 8.25 (d, J=7.6 Hz, 1H), 8.20 (d, J=8.4 Hz,1H), 7.84-7.80 (m, 1H), 7.67-7.63 (m, 1H), 7.59 (d, J=7.2 Hz, 1H), 7.50(d, J=6.4 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 3.09 (t, J=8.0 Hz, 2H),2.33-2.29 (m, 2H).

Example 9: Synthesis of Compound 13

Compound 13 was synthesized by a method similar to that in Example 5,except that methyl 2-(1-(mercaptomethyl)cyclopropyl)acetate was replacedwith the corresponding compound in step 1.

LC-MS (ES, m/z): 383 [M+H]⁺. H-NMR (300 MHz, d₆-DMSO, ppm): δ 7.19-7.21(d, J=5.7 Hz, 1H), 7.45-7.56 (m, 3H), 7.67-7.72 (m, 3H), 7.83-7.90 (m,2H), 8.22-8.30 (m, 2H), 8.60-8.62 (d, J=6.3 Hz, 2H).

Example 10: Synthesis of Compound 14

Compound 14 was synthesized by a method similar to that in Example 5,except that methyl 2-(1-(mercaptomethyl)cyclopropyl)acetate was replacedwith the corresponding compound in step 1.

LC-MS (ES, m/z): 383 [M+H]⁺. H-NMR (300 MHz, d₆-DMSO, ppm): δ 7.02-7.04(d, J=5.7 Hz, 1H), 7.58-7.78 (m, 5H), 7.87-7.91 (m, 2H), 8.01-8.03 (d,J=7.8 Hz, 1H), 8.24-8.27 (d, J=8.4 Hz, 1H), 8.31-8.34 (d, J=7.5 Hz, 1H),8.54-8.57 (m, 2H).

Example 11: Synthesis of Compound 15

Compound 15 was synthesized by a method similar to that in Example 5,except that methyl 2-(1-(mercaptomethyl)cyclopropyl)acetate was replacedwith the corresponding compound in step 1.

LC-MS (ES, m/z): 383 [M+H]⁺. H-NMR (300 MHz, CD₃OD, ppm): δ 7.31-7.33(d, J=6.3 Hz, 1H), 7.62-7.65 (d, J=8.1 Hz, 2H), 7.72-7.79 (m, 3H),7.86-7.91 (m, 1H), 8.12-8.15 (d, J=8.4 Hz, 2H), 8.19-8.22 (d, J=7.5 Hz,1H), 8.35-8.37 (d, J=8.4 Hz, 1H), 8.55-8.57 (d, J=6.3 Hz, 1H), 8.63 (s,1H).

Example 12: Synthesis of Compound 20

Step 1: Synthesis of 4-(4-chloropyridin-3-yl)benzonitrile (20-b)

3-bromo-4-chloropyridine (573 mg, 3 mmol), aqueous solution of sodiumcarbonate (6 mL, 12 mmol, 2 M), 4-cyanophenylboronic acid (441 mg, 3mmol) and tetrakis(triphenylphosphine)palladium (0) (173 mg, 0.15 mmol)were added to dioxane (18 mL) in a single-necked flask (50 mL), and thenpurged with nitrogen 3 times, the mixture was heated to 80° C. andreacted for 5 hours. The reaction solution was cooled, added with ethylacetate (100 mL), and washed with water (100 mL) and brine (100 mL). Theorganic phase was dried, filtered, concentrated, and purified bypreparative silica gel plate (ethyl acetate/petroleum ether: 1/4) toyield a yellow solid product.

Step 2: Synthesis of methyl2-(1-(((3-(4-cyanophenyl)pyridin-4-yl)thio)methyl)cyclopropyl)acetate(20-c)

Methyl 2-(1-(mercaptomethyl)cyclopropyl)acetate (840 mg, 5.25 mmol),potassium carbonate (1.45 g, 10.5 mmol) and4-(4-chloropyridin-3-yl)benzonitrile (450 mg, 2.1 mmol) were dissolvedin dimethyl formamide (20 mL) in a single-necked flask (50 mL), themixture was heated to 130° C. and reacted for 0.5 hour. The reactionsolution was cooled, added with ethyl acetate (100 ml), and washed withwater (100 ml) and brine (100×3 mL). The organic phase was dried,filtered, concentrated, and purified by preparative silica gel plate(ethyl acetate/petroleum ether: 1/2) to yield a yellow oily product.

Step 3: Synthesis of2-(1-(((3-(4-cyanophenyl)pyridin-4-yl)thio)methyl)cyclopropyl)aceticacid (20)

Methyl2-(1-(((3-(4-cyanophenyl)pyridin-4-yl)thio)methyl)cyclopropyl)acetate(67 mg, 0.2 mmol) and aqueous solution of sodium hydroxide (0.5 mL, 0.5mmol, 1 M) were added to methanol (3 mL) in a single-necked flask (50mL), and the mixture was reacted at room temperature for 5 hours. Thereaction solution was adjusted to pH=3 with concentrated hydrochloricacid, concentrated and purified by preparative reverse-phasechromatography to yield a white solid product.

LC-MS (ES, m/z): 325 [M+H]⁺; H-NMR (400 MHz, CDCl₃, ppm): δ 8.42 (s,1H), 8.24 (s, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H),7.35-7.33 (m, 1H), 3.19 (s, 2H), 2.38 (s, 2H), 0.62-0.60 (m, 4H).

Example 13: Synthesis of Compound 17

Step 1: Synthesis of methyl 1-(hydroxymethyl)cyclobutanecarboxylate(17-b)

1-(hydroxymethyl)cyclobutanecarboxylic acid (390 mg, 3 mmol) wasdissolved in methanol (20 mL) in a single-necked flask (50 mL), thionylchloride (1.7 g, 15 mmol) was added thereto at 0° C., then the mixturewas stirred at 65° C. for 4 hours. The reaction solution was cooled,concentrated, and extracted by addition of ethyl acetate (50 mL), andwashed with aqueous solution of sodium bicarbonate (20 mL) and brine (10mL). The organic phase was dried, filtered and concentrated to yield ayellow oily product.

Step 2: Synthesis of methyl1-(((methylsulfonyl)oxy)methyl)cyclobutanecarboxylate (17-c)

17-b (124 mg, 0.86 mmol) was dissolved in dichloromethane (6 mL) in asingle-necked flask (50 mL), N,N-diisopropylethylamine (332 mg, 2.6mmol) and methane sulfonyl chloride (137 mg, 1.2 mmol) were addedthereto at 0° C., then the mixture was stirred at room temperature for 4hours. The reaction solution was washed with water (20 mL) and aqueoussolution of sodium bicarbonate (15 mL). The organic phase was dried,filtered and concentrated to yield a yellow oily product.

Step 3: Synthesis of methyl1-(((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)methyl)cyclobutanecarboxylate(17-d)

1-b (400 mg, 1.5 mmol) was dissolved in N,N-dimethylformamide (10 mL) ina single-necked flask (50 mL), sodium sulfide (234 mg, 4.5 mmol) wasadded thereto, and the mixture was reacted at 130° C. for 2 hours. Thereaction solution was cooled and added with water (30 mL), after that,the reaction solution was adjusted to pH=4 with 1 N aqueous solution ofhydrochloric acid, added with ethyl acetate (50 mL), then organic phasewas washed with water (30 mL) and brine (30 mL). The organic phase wasdried, filtered, and concentrated to yield a yellow solid product.

The above yellow solid product (100 mg, 0.38 mmol), potassium carbonate(210 mg, 1.52 mmol) and 17-c (200 mg, 0.9 mmol) were added toN,N-dimethylformamide (10 mL) in a single-necked flask (50 mL), and themixture was reacted at 60° C. for 2 hours. The reaction solution wascooled, added with ethyl acetate (50 mL), and washed with water (30 mL)and brine (30 mL). The organic phase was dried, filtered, concentratedand purified by preparative silica gel plate (ethyl acetate/petroleumether: 1/1) to yield a yellow solid product.

Step 4: Synthesis of1-(((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)methyl)cyclobutanecarboxylicacid (17)

17-d (64 mg, 0.165 mmol) and 1 M of aqueous solution of lithiumhydroxide (0.82 mL, 0.82 mmol) were added to tetrahydrofuran (4 mL) in asingle-necked flask (50 mL), and the mixture was reacted at roomtemperature for 36 hours. The reaction solution was adjusted to pH=4with 1 N of hydrochloric acid, then added with ethyl acetate (50 mL),and washed with water (20 mL). The organic phase was dried, filtered,concentrated and purified by preparative silica gel plate (ethylacetate/petroleum ether: 2/1) to yield a white solid product.

LC-MS (ES, m/z): 375 [M+H]⁺. H-NMR (400 MHz, DMSO-d₆, ppm): δ 12.42 (s,1H), 8.56 (d, J=5.2 Hz, 1H), 8.18-8.26 (m, 3H), 7.83 (m, 1H), 7.63 (m,2H), 7.55 (d, J=7.2 Hz, 1H), 7.44 (d, J=8.8 Hz, 1H), 3.42 (s, 2H), 2.20(m, 2H), 1.86 (m, 4H).

Example 14: Synthesis of Compound 7

Compound 7 was synthesized by a method similar to that in Example 13,except that 1-(hydroxymethyl)cyclobutanecarboxylic acid was replacedwith the corresponding compound in step 1.

LC-MS (ES, m/z): 361 [M+H]⁺. H-NMR (300 MHz, CD₃OD, ppm): δ 2.20-2.29(m, 2H), 2.85-2.95 (m, 2H), 3.20-3.23 (m, 1H), 4.21-4.25 (m, 1H),7.59-7.71 (m, 4H), 7.82-7.87 (t, J=7.5 Hz, 1H), 8.16-8.18 (d, J=7.2 Hz,1H), 8.33-8.35 (d, J=8.4 Hz, 1H), 8.47 (m, 1H), 8.64 (m, 1H).

Example 15: Synthesis of Compound 16

Compound 16 was synthesized by a method similar to that in Example 13,except that 1-(hydroxymethyl)cyclobutanecarboxylic acid was replacedwith the corresponding compound in step 1.

LC-MS (ES, m/z): 389 [M+H]⁺. H-NMR (400 MHz, DMSO-d6, ppm): δ 8.55 (brs, 1H), 8.18-8.24 (m, 3H), 7.83 (br s, 1H), 7.55-7.59 (m, 3H), 7.44 (brs, 1H), 3.24 (br s, 2H), 1.87 (br s, 2H), 1.54-1.50 (m, 6H).

Example 16: Synthesis of Compound 11

Step 1: Synthesis of (1-((ethoxycarbonyl)methyl)cyclopropyl)methylmethanesulfonate (11-b)

Ethyl 2-(1-(hydroxymethyl)cyclopropyl)acetate (288 mg, 2 mmol) andtriethylamine (404 mg, 4 mmol) were dissolved in dichloromethane (3 mL)in a single-necked flask (50 mL), methanesulfonyl chloride (342 mg, 3mmol) was added thereto under ice water bath condition, then the mixturewas held at room temperature and reacted for 3 hours. Then, the reactionsolution was added with ethyl acetate (50 mL), and washed with water (50mL) and brine (50 mL). The organic phase was dried, filtered, andconcentrated to yield a yellow oily product.

Step 2: Synthesis of ethyl2-(1-((2-bromophenylthio)methyl)cyclopropyl)acetate (11-c)

(1-((ethoxycarbonyl)methyl)cyclopropyl)methyl methanesulfonate (340 mg,1.5 mmol), anhydrous potassium carbonate (242 mg, 1.75 mmol) and2-bromobenzenethiol (235 mg, 1.25 mmol) were dissolved in dimethylformamide (25 mL) in a single-necked flask (50 mL), and the mixture wasreacted at room temperature for 12 hours. Then, the reaction solutionwas added with ethyl acetate (100 ml), and washed 3 times with water (50mL) and brine (50 mL). The organic phase was dried, filtered,concentrated, and purified by preparative silica gel plate (ethylacetate/petroleum ether: 1/7) to yield a yellow oily product.

Step 3: Synthesis of ethyl2-(1-((2-(4-cyanophenyl)phenylthio)methyl)cyclopropyl)acetate (11-d)

Ethyl 2-(1-((2-bromophenylthio)methyl)cyclopropyl)acetate (65 mg, 0.2mmol), aqueous solution of sodium carbonate (0.4 mL, 0.8 mmol, 2 M),4-cyanophenylboronic acid (30 mg, 0.2 mmol) andtetrakis(triphenylphosphine)palladium (0) (23 mg, 0.02 mmol) were addedto dioxane (2 mL) in a single-necked flask (50 mL), and then purged withnitrogen 3 times, the mixture was heated to 80° C. and reacted for 4hours. Then, the reaction solution was added with ethyl acetate (50 ml),washed with water (50 mL) and brine (50 mL). The organic phase wasdried, filtered, concentrated, and purified by preparative silica gelplate (ethyl acetate/petroleum ether: 1/5) to yield a yellow oilyproduct.

Step 4: Synthesis of2-(1-((2-(4-cyanophenyl)phenylthio)methyl)cyclopropyl)acetic acid(compound 11)

Ethyl 2-(1-((2-(4-cyanophenyl)phenylthio)methyl)cyclopropyl)acetate (50mg, 0.14 mmol) and aqueous solution of sodium hydroxide (1 mL, 1 mmol, 1M) were added to methanol (3 mL) in a single-necked flask (50 mL), andthe mixture was reacted at room temperature for 16 hours. Then, thereaction solution was adjusted to pH=3 with concentrated hydrochloricacid, added with ethyl acetate (50 mL), and washed with water (50 mL)and brine (50 mL). The organic phase was dried, filtered, concentrated,and purified by preparative silica gel plate (ethyl acetate/petroleumether: 2/3) to yield a colorless oily product.

LCMS (ES, m/z): 324 [M+H]⁺. H-NMR (400 MHz, CDCl₃, ppm): δ 7.72 (d,J=8.0 Hz, 2H), 7.56 (d, J=, 8.0 Hz, 2H), 7.48-7.46 (m, 1H), 7.33-7.24(m, 2H), 7.20-7.18 (m, 1H), 2.89 (s, 2H), 2.32 (s, 2H), 0.50-0.42 (m,4H).

Example 17: Synthesis of Compound 21

Compound 21 was synthesized by a method similar to that in Example 16,except that 2-bromobenzenethiol was replaced with the correspondingcompound in step 2.

LC-MS (ES, m/z): 342 [M+H]⁺; H-NMR: (400 MHz, CDCl₃, ppm): δ 7.73-7.70(m, 2H), 7.55-7.50 (m, 3H), 7.06-6.95 (m, 2H), 2.79 (s, 2H), 2.28 (s,2H), 0.45-0.37 (m, 4H).

Example 18: Synthesis of Compound 23

Step 1: Synthesis of ethyl2-(1-((2-(4-cyanophenyl)sulfonyl)methyl)cyclopropyl)acetate (23-a)

Ethyl 2-(1-((4-cyanophenyl)phenylthio)methyl)cyclopropyl)acetate (90 mg,0.25 mmol), and potassium monopersulfate triple salt (473 mg, 0.75 mmol)were dissolved in methanol/water (5 mL, 4/1) in a single-necked flask(50 mL), then the mixture was reacted at room temperature for 24 hours.The reaction solution was added with ethyl acetate (100 mL), washed withwater (50 mL) and brine (50×3 mL). The organic phase was dried,filtered, concentrated, and purified by silica gel plate (ethylacetate/petroleum ether: 1/2) to yield a colorless oily product.

Step 2: Synthesis of2-(1-((2-(4-cyanophenyl)sulfonyl)methyl)cyclopropyl)acetic acid (23)

Ethyl 2-(1-((2-(4-cyanobiphenyl)sulfonyl)methyl)cyclopropyl)acetate (64mg, 0.17 mmol), and aqueous solution of lithium hydroxide (0.4 mL, 0.4mmol, 1 M) were added to methanol (3 mL) in a single-necked flask (50mL), then the mixture was reacted at room temperature for 24 hours. Thereaction solution was adjusted to pH=3 with concentrated hydrochloricacid and purified by preparative reverse-phase chromatography to yield awhite solid product.

LC-MS (ES, m/z): 354 [M−H]⁻; H-NMR: (400 MHz, DMSO-d₆, ppm): δ 8.06 (d,J=7.6 Hz, 1H), 7.86 (d, J=8.0 Hz, 2H), 7.80-7.77 (m, 1H), 7.73-7.69 (m,1H), 7.53 (d, J=8.4 Hz, 2H), 7.38 (d, J=7.2 Hz, 1H), 3.13 (s, 2H), 2.17(s, 2H), 0.35-0.33 (m, 4H).

Example 19: Synthesis of2-(3-(1-cyanonaphthalen-4-yl)pyridin-4-ylamino)acetic acid (compound 24)

4-(4-chloropyridin-3-yl)naphtha-1-carbonitrile (53 mg, 0.2 mmol),2-glycine (37 mg, 0.5 mmol) and phenol (113 mg, 1.2 mmol) were added inturn into a pipe sealing reaction bottle, the mixture was heated to 120degrees and reacted overnight. Then, the reaction solution was cooled toroom temperature, added with ether and filtered. Filter cake waspurified by preparative reverse-phase chromatography to yield a whitesolid product.

LCMS (ES, m/z): 304 [M+H]⁺. H-NMR: (400 MHz, CD₃OD, ppm): δ 8.33-8.31(m, 2H), 8.19-8.15 (m, 2H), 7.84-7.76 (m, 2H), 7.70-7.67 (m, 2H), 7.08(d, J=7.2 Hz, 1H), 4.06 (s, 2H).

Example 20: Synthesis of Compound 25

Compound 25 was synthesized by a method similar to that in Example 19,except that glycine was replaced with the corresponding compound in thestep.

LC-MS (ES, m/z): 332 [M+H]⁺; H-NMR (400 MHz, CD₃OD, ppm): δ 8.19-8.13(m, 4H), 7.85-7.67 (m, 4H), 7.17 (d, J=7.2 Hz, 1H), 1.53 (s, 3H), 1.52(s, 3H).

Example 21: Synthesis of Compound 26

Compound 26 was synthesized by a method similar to that in Example 19,except that glycine was replaced with the corresponding compound in thestep.

LC-MS (ES, m/z): 318 [M+H]⁺; H-NMR: (400 MHz, DMSO-d₆, ppm): δ 8.23-8.17(m, 3H), 7.90 (s, 1H), 7.83-7.79 (m, 1H), 7.65-7.62 (m, 1H), 7.57-7.52(m, 2H), 6.75 (d, J=6.4 Hz, 1H), 5.46 (s, 1H), 3.25-3.23 (m, 2H),2.29-2.28 (m, 2H).

Example 22: Synthesis of Compound 27

Compound 27 was synthesized by a method similar to that in Example 19,except that glycine was replaced with the corresponding compound in thestep.

LC-MS (ES, m/z): 332 [M+H]⁺; H-NMR: (400 MHz, DMSO-d₆, ppm): δ 8.20-8.17(m, 3H), 7.88 (s, 1H), 7.83-7.79 (m, 1H), 7.65-7.62 (m, 1H), 7.57-7.53(m, 2H), 6.73 (d, J=6.0 Hz, 1H), 5.54 (s, 1H), 3.01 (d, J=6.4 Hz, 2H),2.10 (d, J=7.2 Hz, 2H), 1.60-1.56 (m, 2H).

Example 23: Synthesis of Compound 28

4-(4-chloropyridin-3-yl)benzonitrile (67 mg, 0.3 mmol), glycine (56 mg,0.75 mmol) and phenol (169 mg, 1.8 mmol) were added in turn into a pipesealing reaction bottle, the mixture was heated to 120 degrees andreacted overnight. The reaction solution was cooled to room temperature,added with ether and filtered. Filter cake was purified by preparativereverse-phase chromatography to yield a white solid product.

LCMS (ES, m/z): 254 [M+H]⁺; H-NMR: (400 MHz, CD₃OD, ppm): δ 8.47 (br s,2H), 8.15 (d, J=6.8 Hz, 1H), 8.00 (s, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.71(d, J=8.0 Hz, 1H), 6.80 (d, J=6.8 Hz, 1H), 3.81 (s, 2H).

Example 24: Synthesis of Compound 29

Step 1: Synthesis of ethyl2-(1-(((3-bromopyridin-4-yl)oxy)methyl)cyclopropyl)acetate (29-a)

3-bromopyridin-4-ol (500 mg, 2.9 mmol) was dissolved in tetrahydrofuran(10 mL) in a three-necked flask (100 mL), ethyl2-(1-hydroxymethyl)cyclopropyl)acetate (428 mg, 2.9 mmol),triphenylphosphine (909 mg, 3.5 mmol) and diethylazodicarboxylate (609mg, 3.5 mmol) were added thereto in turn at 0° C. under the protectionof nitrogen, and then the mixture was heated to room temperature andallowed to carry out Mitsunobu Reaction for 16 hours. The reactionsolution was directly concentrated, and purified by preparative silicagel plate (ethyl acetate/petroleum ether: 2/1) to yield a white solid.

Step 2: Synthesis of ethyl2-(1-(((3-(4-cyanophenyl)pyridin-4-yl)oxy)methyl)cyclopropyl)acetate(29-b)

Ethyl 2-(1-(((3-bromopyridin-4-yl)oxy)methyl)cyclopropyl)acetate (29-a)(90 mg, 0.29 mmol), aqueous solution of sodium carbonate (1 mL, 2 mmol,2 M), 4-cyanophenylboronic acid (43 mg, 0.29 mmol) andtetrakis(triphenylphosphine)palladium (0) (33 mg, 0.03 mmol) were addedto dioxane (3 mL) in a single-necked flask (50 mL), purged with nitrogen3 times, and then the mixture was heated to 80° C. and reacted for 12hours. The reaction solution was cooled to room temperature, added withethyl acetate (50 mL), and washed with water (50 mL) and brine (50 mL).The organic phase was dried, filtered, concentrated, and purified bypreparative silica gel plate (dichloromethane/methanol: 20/1) to yield ayellow oily product.

Step 3: Synthesis of2-(1-(((3-(4-cyanophenyl)pyridin-4-yl)oxy)methyl)cyclopropyl)acetic acid(29)

Ethyl2-(1-(((3-(4-cyanophenyl)pyridin-4-yl)oxy)methyl)cyclopropyl)acetate (60mg, 0.18 mmol) and lithium hydroxide (41 mg, 0.97 mmol) were added totetrahydrofuran/water (3 mL/1 mL) in a single-necked flask (50 mL), andthe mixture was reacted at room temperature for 16 hours. The reactionsolution was adjusted to pH=4 with concentrated hydrochloric acid, addedwith ethyl acetate (50 mL), and washed with water (50 mL) and brine (50mL). The organic phase was dried, filtered, concentrated, and purifiedby preparative silica gel plate (dichloromethane/methanol: 20/1) toyield a white solid product.

LC-MS (ES, m/z): 309 [M+H]⁺. H-NMR: (400 MHz, CDCl₃, ppm): δ 8.05 (d,J=2.0 Hz, 1H), 7.83-7.75 (m, 5H), 6.57-6.55 (m, 1H), 4.07 (s, 2H), 2.22(s, 2H), 0.84-0.82 (m, 2H), 0.73-0.72 (m, 2H).

Example 25: Synthesis of Compound 30

Compound 30 was synthesized by a method similar to that in Example 24,except that (4-cyanophenyl)boronic acid was replaced with thecorresponding compound in step 2.

LC-MS (ES, m/z): 359 [M+H]⁺; H-NMR (400 MHz, CD₃OD, ppm): δ 8.22 (d,J=8.4 Hz, 1H), 8.05 (d, J=7.6 Hz, 1H), 8.02-8.00 (m, 2H), 7.82 (d, J=8.4Hz, 1H), 7.75 (m, 1H), 7.62 (m, 1H), 7.54 (d, J=7.6 Hz, 1H), 6.61 (d,J=7.2 Hz, 1H), 4.12-4.09 (m, 2H), 2.25 (s, 2H), 0.81 (m, 2H), 0.71 (m,2H).

Example 26: Synthesis of Compound 31

Step 1: Synthesis of methyl2-(3-bromopyridin-4-yloxy)-2-methylpropanoate (31-a)

Methyl 2-bromo-2-methylpropanoate (724 mg, 4 mmol), potassium carbonate(828 mg, 6 mmol) and 3-bromo-4-hydroxypyridine (348 mg, 2 mmol) weredissolved in dimethyl formamide (20 mL) in a single-necked flask (50mL), then the mixture was reacted at 60° C. for 12 hours. The reactionsolution was cooled to room temperature, added with ethyl acetate (100mL), and washed with water (50 mL) and brine (50×3 mL). The organicphase was dried, filtered, concentrated, and purified by silica gelcolumn (dichloromethane/methanol: 50/1-20/1) to yield a colorless oilyproduct.

Step 2: Synthesis of2-(3-(4-cyanophenyl)pyridin-4-yloxy)-2-methylpropanoic acid (31)

Methyl 2-(3-bromopyridin-4-yloxy)-2-methylpropanoate (109 mg, 0.4 mmol),aqueous solution of sodium carbonate (0.8 mL, 1.6 mmol, 2 M),4-cyanophenylboronic acid (59 mg, 0.4 mmol) andtetrakis(triphenylphosphine)palladium (0) (46 mg, 0.04 mmol) were addedto dioxane (2.4 mL) in a single-necked flask (50 mL), purged withnitrogen 3 times, and then the mixture was heated to 80° C. and reactedfor 12 hours. The reaction solution was cooled to room temperature,adjusted to pH=4, added with ethyl acetate (100 mL), and washed withwater (100 mL) and brine (100 mL). The organic phase was dried,filtered, concentrated, and purified by preparative reverse-phasechromatography to yield a white solid product.

LC-MS (ES, m/z): 283 [M+H]⁺; H-NMR (400 MHz, CD₃OD, ppm): δ 8.35-8.30(m, 2H), 7.82-7.77 (m, 4H), 6.98-6.97 (m, 1H), 1.59 (s, 6H).

Example 27: Synthesis of Compound 10

Step 1: Synthesis of 1-(4-chloropyridin-3-yl)isoquinoline-4-carbonitrile(10-a)

In a three-necked flask (100 mL), under the protection of nitrogen,1-chloroisoquinoline-4-carbonitrile (450 mg, 2.39 mmol) was dissolved intoluene (30 mL) and water (3 mL), and4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (687mg, 2.87 mmol), sodium carbonate (761 mg, 7.18 mmol) and palladiumcatalyst tetrakis(triphenylphosphine)palladium (0) (138 mg, 0.12 mmol)were added thereto, then the mixture was heated to 95° C. and reactedfor 2 hours. The reaction solution was cooled, and the reaction wasquenched by addition of 50 mL of ice water, then the reaction solutionwas extracted with ethyl acetate (100 mL, 3 times), reversely washedwith saturated brine (100 mL, 3 times), dried over anhydrous sodiumsulfate, rotary evaporated, and purified by column chromatography(petroleum ether/ethyl acetate=10:1˜petroleum ether/ethylacetate/dichloromethane=1:1:1), to yield an off-white solid product.

Step 2: Synthesis of methyl2-((3-(4-cyanoisoquinolin-1-yl)pyridin-4-yl)thio)-2-methylpropanoate(10-b)

In a three-necked flask (100 mL), under the protection of nitrogen,1-(4-chloropyridin-3-yl)isoquinoline-4-carbonitrile (110 mg, 0.41 mmol)obtained in step 2 was dissolved in dimethyl formamide (20 mL), thesolution was then added with sodium sulfide (194 mg, 2.49 mmol), themixture was heated to 130° C. and reacted for about 1.5 hours, thencooled to room temperature, followed by addition of anhydrous potassiumcarbonate (286 mg, 2.07 mmol) and then methyl1-(bromomethyl)cyclopropanecarboxylate (224 mg, 1.24 mmol), the mixturewas then heated to 130° C. and allowed to further react for about 1.5hours until the reaction was completed. The reaction solution was cooledand poured into 50 mL of ice water to quench the reaction, then thereaction solution was extracted with ethyl acetate (50 mL, 3 times), theorganic phase was dried over anhydrous sodium sulfate, rotatoryevaporated, and purified through column chromatography (petroleumether/ethyl acetate=10:1˜petroleum ether/ethylacetate/dichloromethane=1:1:1), to yield a yellow oily product.

Step 3: Synthesis of2-((3-(4-cyanoisoquinolin-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid(compound 10)

methyl2-((3-(4-cyanoisoquinolin-1-yl)pyridin-4-yl)thio)-2-methylpropanoate (60mg, 0.17 mmol) obtained in step 3, lithium hydroxide (12 mg, 0.50 mmol),tetrahydrofuran (24 mL) and water (8 mL) were added into a three-neckedflask (100 mL) under the protection of N₂, the mixture was reacted atroom temperature overnight. Tetrahydrofuran was removed byconcentration; aqueous phase was extracted 3 times with dichloromethane(50 mL) and collected. Then the aqueous phase was adjusted to pH=4-5with 2 N of hydrochloric acid regulating system and extracted withdichloromethane (100 mL, 3 times); the organic phase was combined, thendried with sodium sulfate, and rotatory evaporated. The crude productwas subject to high pressure to yield a white solid product.

LC-MS (ES, m/z): 350 [M+H]⁺; H-NMR (300 MHz, CD₃OD, ppm): δ 1.55 (s,6H), 7.83-7.95 (m, 3H), 8.09-8.14 (m, 1H), 8.33-8.36 (d, J=8.4 Hz, 1H),8.67-8.74 (m, 2H), 9.09 (s, 1H).

Example 28: Synthesis of Compound 8

Step 1: Synthesis of 1-(4-chloropyridin-3-yl)-1H-indole-3-carbonitrile(8-a)

In a three-necked flask (100 under the protection of N₂, copper acetate(1800 mg, 9.9 mmol) and pyridine (1200 mg, 15.1 mmol) were sequentiallyadded to 1H-indole-3-carbonitrile (700 mg, 4.9 mmol) and4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1300mg, 5.4 mmol) which were dissolved in dimethyl formamide (50 mL), thenthe mixture was stirred at room temperature.4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (700mg, 3.0 mmol) was replenished every 4 hours, 5 times in total. Thereaction solution was poured into 100 mL of ice water to make thereaction quenched, then the reaction solution was extracted with ethylacetate (150 mL, 3 times) and washed with saturated brine (150 mL, 3times). The organic phase was dried over anhydrous sodium sulfate,rotatory evaporated and subject to high pressure to yield a white solid.

Step 2: Synthesis of methyl2-((3-(3-cyano-1H-indol-1-yl)pyridin-4-yl)thio)-2-methylpropanoate (8-b)

In a three-necked flask (100 mL), under the protection of N₂,1-(4-chloropyridin-3-yl)-1H-indole-3-carbonitrile (100 mg, 0.39 mmol)obtained in step 1 was dissolved in dimethyl formamide (50 mL), thensodium sulfide (185 mg, 2.37 mmol) was added thereto, the mixture washeated to 130° C. and reacted for about 1 hour, then cooled to roomtemperature, followed by addition of anhydrous potassium carbonate (273mg, 1.98 mmol) and then methyl 1-(bromomethyl)cyclopropanecarboxylate(213 mg, 1.18 mmol), the mixture was heated to 130° C. and allowed tofurther react for about 1.5 hour until the reaction was completed. Thereaction solution was cooled and poured into 100 mL ice water, thus thereaction was quenched. The reaction solution was extracted with ethylacetate (150 mL, 3 times), the organic phase was dried over anhydroussodium sulfate, rotatory evaporated and subject to high pressure toyield a light yellow solid.

Step 3: Synthesis of2-((3-(3-cyano-1H-indol-1-yl)pyridin-4-yl)thio)-2-methylpropanoic acid(compound 8)

Methyl2-((3-(3-cyano-1H-indol-1-yl)pyridin-4-yl)thio)-2-methylpropanoate (50mg, 0.10 mmol) obtained in step 2, lithium hydroxide (11 mg, 0.40 mmol),tetrahydrofuran (24 mL) and water (8 mL) were added into a three-neckedflask (50 mL) under the protection of N₂, and reacted at roomtemperature overnight. Tetrahydrofuran was removed by concentration;aqueous phase was extracted 3 times with dichloromethane (50 mL) andcollected. Then the aqueous phase was adjusted to pH=4-5 with 2N ofhydrochloric acid regulating system and extracted with dichloromethane(100 mL, 3 times); the organic phase was combined, dried over sodiumsulfate and then rotatory evaporated. The crude product was subject tohigh pressure to yield a light yellow solid.

LC-MS (ES, m/z): 338 [M+H]⁺; H-NMR (300 MHz, CD₃OD, ppm): δ1.54 (s, 6H),7.13-16 (m, 1H), 7.36-43 (m, 2H), 7.76-7.82 (m, 2H), 8.13 (s, 1H),8.63-8.68 (m, 2H).

Example 29: Synthesis of Compound 9

Compound 9 was synthesized by a method similar to that in Example 28,except that 1H-indole-3-carbonitrile was replaced with the correspondingcompound in step 1.

LC-MS (ES, m/z): 354 [M+H]⁺; H-NMR (300 MHz, CD₃OD, ppm): δ 1.12-1.14(m, 4H), 1.51 (s, 6H), 2.32-2.41 (m, 1H), 7.16-7.19 (d, J=8.4 Hz, 1H),7.24-7.28 (m, 1H), 7.43-7.48 (m, 1H), 7.685 (m, 1H), 7.88-7.91 (d, J=8.1Hz, 1H), 8.50 (br s, 2H).

Example 30: Synthesis of Compound 22

Step 1: Synthesis of methyl2-(1-((3-bromopyridin-4-ylthio)methyl)cyclopropyl)acetate (22-a)

In a single-necked flask (50 mL), methyl2-(1-(mercaptomethyl)cyclopropyl)acetate (2 g, 12.5 mmol), potassiumcarbonate (3.45 g, 25 mmol), and 3-bromo-4-chloropyridine (955 mg, 5mmol) were dissolved in dimethyl formamide (30 mL), the mixture washeated to 130° C. and reacted for 2 hours. The reaction solution wascooled to room temperature, added with ethyl acetate (100 ml), andwashed with water (100 mL) and brine (100 mL, 3 times). The organicphase was dried, filtered, concentrated and purified by silica gelcolumn (ethyl acetate/petroleum ether: 1/10-1/6) to yield a yellow solidproduct.

Step 2: Synthesis of methyl2-(1-((3-(4-(hydroxymethyl)phenylpyridin-4-yl)thio)methyl)cyclopropyl)acetate(22-b)

Methyl 2-(1-((3-bromopyridin-4-ylthio)methyl)cyclopropyl)acetate (160mg, 0.5 mmol), aqueous solution of sodium carbonate (1 mL, 2 mmol, 2 M),4-hydroxymethylphenylboric acid (76 mg, 0.5 mmol) andtetrakis(triphenylphosphine)palladium(0) (60 mg, 0.05 mmol) were addedto dioxane (3 mL) in a single-necked flask (50 mL), purged with nitrogen3 times, and then the mixture was heated to 80° C. and reacted for 12hours. The reaction solution was cooled to room temperature, added withethyl acetate (100 ml), and washed with water (100 mL) and brine (100mL). The organic phase was dried, filtered, concentrated and purified bypreparative silica gel plate (ethyl acetate/petroleum ether: 1/1) toyield a yellow solid product.

Step 3: Synthesis of2-(1-((3-(4-(hydroxymethyl)phenyl)pyridin-4-ylthio)methyl)cyclopropyl)aceticacid (22)

In a single-necked flask (50 mL), methyl2-(1-(((3-(4-(hydroxymethyl)phenyl)pyridin-4-yl)thio)methyl)cyclopropyl)acetate(140 mg, 0.4 mmol) and aqueous solution of aluminum hydroxide (0.8 mL,0.8 mmol, 1 M) were added to methanol (3 mL), then the mixture wasreacted at room temperature for 2 hours. The reaction solution wasadjusted to pH=3 with concentrated hydrochloric acid, concentrated andpurified by preparative silica gel plate (dichloromethane/methanol:10/1) to yield a white solid product.

LC-MS (ES, m/z): 330 [M+H]⁺; H-NMR (400 MHz, DMSO-d₆, ppm): δ 8.35 (d,J=6.4 Hz, 1H), 8.19 (s, 1H), 7.42-7.33 (m, 5H), 5.25 (s, 1H), 4.50 (d,J=6.4 Hz, 2H), 3.12 (s, 2H), 2.24 (s, 2H), 0.52-0.50 (m, 4H).

Example 31: Synthesis of Compound 36

Step 1: Synthesis of 3-(4-bromophenyl)oxetan-3-ol (36-a)

In a three-necked flask (50 mL), under the protection of nitrogen,1,4-dibromobenzene (600 mg, 2.55 mmol) was dissolved in tetrahydrofuran(15 mL), then the solution was cooled to 78° C. and added withn-butyllithium (1.05 mL, 2.55 mmol, 2.5 M in hexane). The mixture wasreacted for 0.5 hour, then added dropwise with oxetan-3-one (153 mg,2.55 mmol), and the resulting mixture was further reacted for 3 hours.The reaction was quenched with saturated aqueous solution of ammoniumchloride (20 mL), the reaction solution was added with ethyl acetate (50ml), then washed with brine (10 mL). The organic phase was dried,filtered, concentrated and purified by preparative silica gel plate(petroleum ether/ethyl acetate: 3/1) to yield a white solid.

Step 2: Synthesis of3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol(36-b)

36-a (300 mg, 1.2 mmol), potassium acetate (323 mg, 3.3 mmol),bis(pinacolato)diboron (B₂(pin)₂) (420 mg, 1.6 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (100 mg, 0.12mmol) were added to 1,4-dioxane (15 mL) in a single-necked flask (100mL), purged with nitrogen 3 times, and then the mixture was heated to90° C. and reacted for 16 hours. The reaction solution was cooled, addedwith ethyl acetate (60 ml), and washed with water (40 mL). The organicphase was dried, filtered, concentrated and purified by silica gelcolumn (petroleum ether/ethyl acetate: 3/1) to yield a white solid.

Step 3: Synthesis of methyl2-(1-(((3-(4-(3-hydroxyoxetan-3-yl)phenyl)pyridin-4-yl)thio)methyl)cyclopropyl)acetate(36-c)

36-b (150 mg, 0.54 mmol), aqueous solution of sodium carbonate (2.2 mL,2.2 mmol, 1 M), 22-a (170 mg, 0.54 mmol), andtetrakis(triphenylphosphine)palladium(0) (62 mg, 0.054 mmol) were addedto dioxane (8 mL) in a single-necked flask (100 mL), and then purgedwith nitrogen 3 times. The mixture was heated to 80° C. and reacted for16 hours. The reaction solution was cooled, added with ethyl acetate (50mL), and washed with water (40 mL). The organic phase was dried,filtered, concentrated and purified by preparative silica gel plate(petroleum ether/ethyl acetate: 1/1) to yield a white solid.

Step 4: Synthesis of2-(1-(((3-(4-(3-hydroxyoxetan-3-yl)phenyl)pyridin-4-yl)thio)methyl)cyclopropyl)aceticacid (36)

Experimental process: In a single-necked flask (50 mL), 36-c (70 mg,0.18 mmol) and 1 M of aqueous solution of lithium hydroxide (1 mL, 1mmol) were added to tetrahydrofuran (3 mL), and the mixture was reactedat room temperature for 16 hours. The reaction solution was adjusted topH=4 with 1 N of hydrochloric acid, added with chloroform-d/isopropanol(30 mL/10 mL) and washed with brine (50 mL). The organic phase wasdried, filtered, concentrated and purified by preparative reverse-phasechromatography to yield a white solid product.

LC-MS (ES, m/z): 372 [M+H]⁺; H-NMR (400 MHz, DMSO-d6, ppm): δ 8.35 (d,J=5.6 Hz, 1H), 8.20 (s, 1H), 7.68 (m, 2H), 7.43 (m, 2H), 7.35 (d, J=5.2Hz, 1H), 6.41 (br s, 1H), 4.77 (d, J=6.4 Hz, 2H), 4.72 (d, J=6.8 Hz,2H), 3.15 (s, 2H), 2.22 (s, 2H), 0.49 (m, 4H).

Example 32: Synthesis of Compound 35

Step 1: Synthesis of 3-(4-(4-chloropyridin-3-yl)phenyl)oxetan-3-ol(35-a)

36-b (200 mg, 0.72 mmol), aqueous solution of sodium carbonate (1.4 mL,2.8 mmol, 2 M), 3-bromo-4-chloropyridine (139 mg, 0.72 mmol), andtetrakis(triphenylphosphine)palladium(0) (83 mg, 0.072 mmol) were addedto dioxane (6 mL) in a single-necked flask (50 mL), purged with nitrogen3 times, and then the mixture was heated to 80° C. and reacted for 16hours. The reaction solution was added with ethyl acetate (50 ml) andwashed with water (40 mL). The organic phase was dried, filtered,concentrated and purified by preparative silica gel plate (ethylacetate/petroleum ether: 1/1) to yield a white solid product.

Step 2: Synthesis of2-((3-(4-(3-hydroxyoxetan-3-yl)phenyl)pyridin-4-yl)thio)-2-methylpropanoicacid (35)

In a single-necked flask (50 mL), 35-a (140 mg, 0.54 mmol) and sodiumsulfide (125 mg, 1.6 mmol) were added to dimethyl formamide (6 mL), themixture was heated to 130° C. and reacted for 1 hour. After beingcooled, the reaction solution was added with anhydrous potassiumcarbonate (220 mg, 1.6 mmol), methyl 2-bromoisobutyrate (289 mg, 1.6mmol), and the resulting solution was reacted for another 1 hour at 130°C. The reaction solution was added with ether (50 mL) and water (50 mL),aqueous phase was adjusted to pH=4 with dilute hydrochloric acid (1 M),then extracted by addition of chloroform-d/isopropanol (30 mL/10 mL),and washed with brine (20 mL). The organic phase was dried, filtered,concentrated and preparatively purified to yield a white solid product.

LC-MS (ES, m/z): 346 [M+H]⁺; H-NMR (400 MHz, DMSO-d6, ppm): δ 8.40 (d,J=5.6 Hz, 1H), 8.29 (s, 1H), 7.66 (m, 2H), 7.38 (m, 3H), 6.42 (br s,1H), 4.77 (d, J=6.4 Hz, 2H), 4.71 (d, J=6.8 Hz, 2H), 1.44 (s, 6H).

Example 33: Synthesis of Compound 34

Step 1: Synthesis of methyl 4-(4-chloropyridin-3-yl)benzoate (34-a)

3-bromo-4-chloropyridine (764 mg, 4 mmol), aqueous solution of sodiumcarbonate (8 mL, 16 mmol, 2 M), 4-(methoxycarbonyl)phenylboronic acid(860 mg, 4 mmol), potassium acetate (392 mg, 4 mmol), andtetrakis(triphenylphosphine)palladium(0) (164 mg, 0.2 mmol) were addedto dioxane (24 mL) in a single-necked flask (100 mL), purged withnitrogen 3 times, then the mixture was heated to 80° C. and reacted for12 hours. The reaction solution was added with ethyl acetate (100 mL),and washed with water (100 mL) and brine (100 mL). The organic phase wasdried, filtered, concentrated and purified by silica gel column (ethylacetate/petroleum ether: 1/8-1/4) to yield a white solid product.

Step 2: Synthesis of 1-(4-(4-chloropyridin-3-yl)phenyl)cyclopropanol(34-b)

In a three-necked flask (50 mL), ethylmagnesium bromide (in ether (1 M),6.8 mL, 6.8 mmol) was slowly added dropwise to the solution of 34-a (838mg, 3.4 mmol) and titanium tetraisopropoxide (0.85 g, 3.4 mmol) intoluene (30 mL) under room temperature condition within 30 min, then themixture was reacted for 1 hour. The reaction solution was further addedwith titanium tetraisopropoxide (0.85 g, 3.4 mmol) and ethylmagnesiumbromide (1 M, in Et₂O, 6.8 mL, 6.8 mmol) and reacted for another 0.5hour. The reaction was quenched with water, extracted with ethyl acetate(100 mL) and washed with water (100 mL) and brine (100 mL). The organicphase was dried, filtered, concentrated and purified by preparativereverse-phase chromatography to yield a white solid product.

Step 3: Synthesis of3-(4-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)phenyl)-4-chloropyridine(34-c)

In a single-necked flask (50 mL), under ice bath condition, the solutionof 34-b (150 mg, 0.6 mmol) and imidazole (204 mg, 3 mmol) in dimethylformamide (5 mL) was added with tert-butyldimethylsilyl chloride (453mg, 3 mmol), then the mixture was reacted at room temperature for 2hours. The reaction solution was added with ethyl acetate (50 mL), andwashed with water (50 mL) and brine (50 mL). The organic phase wasdried, filtered, concentrated and purified by silica gel plate (ethylacetate/petroleum ether: 1/4) to yield a white solid product.

Step 4: Synthesis of methyl2-(1-(((3-(4-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)phenyl)pyridin-4-yl)thio)methyl)cyclopropyl)acetate(34-d)

In a single-necked flask (50 mL), 34-c (70 mg, 0.2 mmol), anhydrouspotassium carbonate (138 mg, 1 mmol), and methyl2-(1-(mercaptomethyl)cyclopropyl)acetate (80 mg, 0.5 mmol) weredissolved in dimethyl formamide (3 mL), the mixture was heated to 130°C. and reacted for 0.5 hour. The reaction solution was added with ethylacetate (100 mL), and washed with water (100 mL) and brine (100×3 mL).The organic phase was dried, filtered, concentrated and purified bypreparative silica gel plate (ethyl acetate/petroleum ether: 1/3) toyield a yellow oily product.

Step 5: Synthesis of2-(1-(((3-(4-(1-(tert-butyldimethylsilyl)oxy)cyclopropyl)phenyl)pyridin-4-yl)thio)methyl)cyclopropyl)aceticacid (34-e)

In a single-necked flask (50 mL), 34-d (120 mg, 0.25 mmol) and aqueoussolution of lithium hydroxide (0.75 mL, 0.75 mmol, 1 M) were added tomethanol (3 mL), and reacted for 2 hours at room temperature. Thereaction solution was adjusted to pH=3 with concentrated hydrochloricacid, and concentrated to dryness.

Step 6: Synthesis of2-(1-(((3-(4-(1-hydroxycyclopropyl)phenyl)pyridin-4-yl)thio)methyl)cyclopropyl)aceticacid (34)

In a single-necked flask (50 mL), 34-e (obtained in the last step, 0.25mmol) and tetrabutylammonium fluoride (TBAF) (0.5 mL, 0.5 mmol, 1 M)were added to tetrahydrofuran (3 mL), and reacted at room temperaturefor 0.5 hour. The reaction solution was added with ethyl acetate (50 mL)and washed with water (50 mL) and brine (50×3 mL). The organic phase wasdried, filtered, concentrated and purified by preparative reverse-phasechromatography to yield a white solid product.

LC-MS (ES, m/z): 356 [M+H]⁺; H-NMR (400 MHz, CD₃OD, ppm): δ 8.48 (d,J=6.4 Hz, 1H), 8.35 (s, 1H), 7.93 (d, J=6.8 Hz, 1H), 7.48-7.42 (m, 4H),3.38 (s, 2H), 2.36 (s, 2H), 1.28-1.25 (m, 2H), 1.12-1.09 (m, 2H),0.66-0.65 (m, 4H).

Example 34: Synthesis of Compound 33

Step 1: Synthesis of4-chloro-3-(4-(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)phenyl)pyridine(33-a)

In a single-necked flask (50 mL), the solution of 34-b (50 mg, 0.2 mmol)and p-toluene sulfonic acid (PTSA) (7 mg, 0.04 mmol) in dichloromethane(5 mL) was added with dihydropyran (DHP) (33 mg, 0.4 mmol), and themixture was reacted at room temperature for 12 hours. The reactionsolution was added with ethyl acetate (50 ml), and then washed withwater (50 mL) and brine (50 mL). The organic phase was dried, filtered,concentrated and purified by silica gel plate (ethyl acetate/petroleumether: 1/4) to yield a colorless oily product.

Step 2: Synthesis of methyl2-methyl-2-((3-(4-(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)phenyl)pyridin-4-yl)thio)propanoate(33-b)

In a single-necked flask (50 mL), 33-a (37 mg, 0.11 mmol) and sodiumsulfide (26 mg, 0.33 mmol) were dissolved in dimethyl formamide (4 mL),the mixture was heated to 130° C. and reacted for 1 hour. After beingcooled, the mixture was added with anhydrous potassium carbonate (76 mg,0.55 mmol) and methyl 2-bromoisobutyrate (60 mg, 0.33 mmol), then heatedto 50° C. and the resulting mixture was allowed to further react for 1hour. The reaction solution was added with ethyl acetate (50 mL), andwashed with water (50 mL) and brine (50 mL). The organic phase wasdried, filtered, concentrated and purified by preparative silica gelplate (ethyl acetate/petroleum ether: 1/3) to yield a yellow oilysubstance.

Step 3: Synthesis of2-methyl-2-((3-(4-(1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)phenyl)pyridin-4-yl)thio)propanoicacid (33-c)

In a single-necked flask (50 mL), 33-b (35 mg, 0.08 mmol) and theaqueous solution of lithium hydroxide (0.24 mL, 0.24 mmol, 1 M) wereadded to methanol (3 mL), and reacted for 6 hours at room temperature.The reaction solution was adjusted to pH=5 with concentratedhydrochloric acid, and then concentrated to yield a yellow oilysubstance.

Step 4: Synthesis of2-((3-(4-(1-hydroxycyclopropyl)phenyl)pyridin-4-yl)thio)-2-methylpropanoicacid (33)

In a single-necked flask (50 mL), 33 (25 mg, 0.06 mmol) and p-toluenesulfonic acid (2 mg, 0.01 mmol) were added to methanol (3 mL), andreacted for 1 hour at room temperature. The reaction solution was addedwith ethyl acetate (50 ml), and washed with water (50 mL) and brine(50×3 mL). The organic phase was dried, filtered, concentrated andpurified by preparative silica gel plate (dichloromethane/methanol: 8/1)to yield a light yellow solid product.

LC-MS (ES, m/z): 330 [M+H]⁺; H-NMR (400 MHz, DMSO-d6, ppm): δ 13.17 (s,1H), 8.41 (d, J=6.4 Hz, 1H), 8.29 (s, 1H), 7.33-7.25 (m, 5H), 5.99 (s,1H), 1.44 (s, 6H), 1.13-1.12 (m, 2H), 0.99-0.98 (m, 2H).

Example 35: Synthesis of Compound 37

Step 1: Synthesis of 4′-chloro-[2,3′-bipyridine]-5-nitrile (37-a)

4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (400mg, 1.64 mmol), the aqueous solution of sodium carbonate (3.3 mL, 6.6mmol, 2 M), 6-bromopyridin-3-carbonitrile (300 mg, 1.64 mmol) andtetrakis(triphenylphosphine)palladium (0) (180 mg, 0.16 mmol) were addedto dioxane (10 mL) in a single-necked flask (50 mL), and purged withnitrogen 3 times, and then the mixture was heated to 80° C. and reactedfor 5 hours. The reaction solution was added with ethyl acetate (50 mL),and washed with water (50 mL) and brine (50 mL). The organic phase wasdried, filtered, concentrated and purified by preparative silica gelplate (ethyl acetate/petroleum ether: 1/3) to yield a yellow solidproduct.

Step 2: Synthesis of methyl2-((5-cyano-[2,3′-bipyridine]-4′-yl)thio)-2-methylpropanoate (37-b)

In a single-necked flask (50 mL), 37-a (108 mg, 0.5 mmol) and sodiumsulfide (117 mg, 1.5 mmol) were dissolved in dimethyl formamide (10 mL),the mixture was heated to 130° C. and reacted for 1 hour. After beingcooled, the mixture was further added with anhydrous potassium carbonate(207 mg, 1.5 mmol) and methyl 2-bromoisobutyrate (272 mg, 1.5 mmol), andwas allowed to further react for 1 hour at 130° C. The reaction solutionwas added with ethyl acetate (50 mL), and washed with water (50 mL) andbrine (50 mL). The organic phase was dried, filtered, concentrated andpurified by preparative silica gel plate (ethyl acetate/petroleum ether:1/1) to yield a yellow oily substance.

Step 3: Synthesis of2-((5-cyano-[2,3′-bipyridine]-4′-yl)thio)-2-methylpropanoic acid (37)

In a single-necked flask (50 mL), 37-b (60 mg, 0.19 mmol) and lithiumhydroxide (41 mg, 0.97 mmol) were added to tetrahydrofuran/water (3 mL/1mL) and reacted at room temperature for 6 hours. The reaction solutionwas adjusted to pH=4 with dilute hydrochloric acid (1 M), added withethyl acetate (50 mL) and washed with water (50 mL) and brine (50 mL).The organic phase was dried, filtered, concentrated and preparativelypurified to yield a white solid product.

LC-MS (ES, m/z): 300 [M+H]⁺; H-NMR: (400 MHz, CD₃OD, ppm): δ 9.02 (d,J=2 Hz, 1H), 8.59 (s, 1H), 8.48 (d, J=5.2 Hz, 1H), 8.29-8.26 (m, 1H),7.90-7.88 (m, 1H), 7.62 (d, J=5.6 Hz, 1H), 1.50 (s, 6H).

Example 36: Synthesis of Compound 19

Compound 19 was synthesized by a method similar to that in Example 35,except that 6-bromopyridin-3-carbonitrile was replaced with thecorresponding compound in step 1.

LC-MS (ES, m/z): 314 [M+H]⁺; H-NMR (400 MHz, CD₃OD, ppm): δ 8.81 (d,J=1.6 Hz, 1H), 8.49 (d, J=6.4 Hz, 1H), 8.31 (s, 1H), 8.18 (d, J=1.2 Hz,1H), 7.61 (d, J=6.4 Hz, 1H), 2.22 (s, 3H), 1.53 (s, 6H).

Example 37: Synthesis of Compound 38

Step 1: Synthesis of methyl2-(1-(((5-cyano-[2,3′-bipyridine]-4′-yl)thio)methyl)cyclopropyl)propionate(38-a)

In a single-necked flask (50 mL), 37-a (100 mg, 0.46 mmol) and methyl2-(1-(mercaptomethyl)cyclopropyl)propionate (160 mg, 0.92 mmol) weredissolved in dimethyl formamide (2 mL), anhydrous potassium carbonate(256 mg, 1.84 mmol) was added thereto, and the reaction was carried outat 130° C. for 0.5 hour. The reaction solution was added with ethylacetate (50 mL), and washed with water (50 mL) and brine (50 mL). Theorganic phase was dried, filtered, concentrated and purified bypreparative silica gel plate (ethyl acetate/petroleum ether: 1/1) toyield a white solid.

Step 2: Synthesis of2-(1-(((5-cyano-2,3′-bipyridin-4′-yl)thio)methyl)cyclopropyl)acetic acid(38)

In a single-necked flask (50 mL), 38-a (90 mg, 0.26 mmol) and lithiumhydroxide (41 mg, 0.97 mmol) were added to tetrahydrofuran/water (3 mL/1mL) and reacted at 0° C. for 6 hours. The reaction solution was adjustedto pH=4 with dilute hydrochloric acid (1 M), added with ethyl acetate(50 mL), and washed with water (50 mL) and brine (50 mL). The organicphase was dried, filtered, concentrated and preparatively purified toyield a white solid product.

LC-MS (ES, m/z): 326 [M+H]⁺; H-NMR: (400 MHz, CD₃OD, ppm): 9.11 (d,J=1.6 Hz, 1H), 8.73 (s, 1H), 8.56 (d, J=6.0 Hz, 1H), 8.38 (dd, J=2.0 Hz,J=8.0 Hz, 1H), 8.02-8.04 (m, 2H), 3.44 (s, 2H), 2.39 (s, 2H), 0.67 (m,4H).

Example 38: Synthesis of Compound 39

Step 1: Synthesis of4′-(((1-(carboxymethyl)cyclopropyl)methyl)thio)-[2,3′-bipyridine]-5-carboxylicacid (39)

In a single-necked flask (50 mL), 38-a (40 mg, 0.12 mmol) and lithiumhydroxide (15 mg, 0.36 mmol) were added to tetrahydrofuran/water (3 mL/1mL) and reacted for 16 hours. The reaction solution was adjusted to pH=4with dilute hydrochloric acid (1 M), added with ethyl acetate (50 mL),and washed with water (50 mL) and brine (50 mL). The organic phase wasdried, filtered, concentrated and preparatively purified to yield awhite solid product.

LC-MS (ES, m/z): 345.0 [M+H]⁺; H-NMR: (400 MHz, CD₃OD, ppm): 9.30 (d,J=1.2 Hz, 1H), 8.72 (s, 1H), 8.55 (m, 2H), 8.04 (d, J=6.4 Hz, 1H), 7.95(d, J=8.4 Hz, 1H), 3.45 (s, 2H), 2.39 (s, 2H), 0.67 (m, 4H).

Example 39: Synthesis of Compound 32

Step 1: Synthesis of ethyl 3-(3-bromopyridin-4-yl)propanoate (32-a)

In a single-necked flask (100 mL), under the protection of nitrogen,3-bromo-4-methylpyridine (500 mg, 2.9 mmol) was dissolved in thetetrahydrofuran (10 mL), the solution was then cooled to −78° C., andadded with homemade lithium diisopropylamide (LDA) (3.5 mL, 3.5 mmol),after reacted for 1 hour, ethyl 2-bromoacetate (1.22 g, 7.3 mmol) wasfurther added dropwise thereto and reacted for another 2 hours. Thereaction was quenched with saturated sodium bicarbonate solution, thereaction solution was added with ethyl acetate (50 mL), and washed withwater (50 mL) and brine (50 mL). The organic phase was dried, filtered,concentrated and purified by preparative silica gel plate (petroleumether/ethyl acetate: 2/1) to yield a yellow oily substance.

Step 2: Synthesis of ethyl 3-(3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)propanoate (32-b)

32-a (100 mg, 0.39 mmol), the aqueous solution of sodium carbonate (0.8mL, 1.6 mmol, 2 M),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-cyano-naphthalene (108mg, 0.39 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (29 mg, 0.04 mmol) were added to dimethylformamide (3 mL) in a single-necked flask (50 mL), purged with nitrogen3 times, and then the mixture was heated to 130° C. and reacted for 5hours. The reaction solution was added with ethyl acetate (50 mL), andwashed with water (50 mL) and brine (50 mL). The organic phase wasdried, filtered, concentrated and purified by preparative silica gelplate (petroleum ether/ethyl acetate: 1/1) to yield a light yellowsolid.

Step 3: Synthesis of 3-(3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)propanoic acid (32)

In a single-necked flask (50 mL), 32-b (30 mg, 0.1 mmol) and lithiumhydroxide (41 mg, 0.97 mmol) were added to tetrahydrofuran/water (3 mL/1mL), and the mixture was reacted at room temperature for 16 hours. Thereaction solution was adjusted to pH=4 with dilute hydrochloric acid(1M), added with ethyl acetate (50 mL), and then washed with water (50mL) and brine (50 mL). The organic phase was dried, filtered,concentrated, and preparatively purified to yield a white solid product.

LC-MS (ES, m/z): 301 [M−H]⁻; H-NMR: (400 MHz, CD₃OD, ppm): δ 8.60 (d,J=5.2 Hz, 1H), 8.36 (s, 1H), 8.32-8.30 (m, 1H), 8.15-8.13 (m, 1H),7.83-7.79 (m, 1H), 7.69-7.65 (m, 1H), 7.63-7.59 (m, 2H), 7.51-7.48 (m,1H), 2.73-2.56 (m, 2H), 2.45-2.40 (m, 2H).

Example 40: Synthesis of Compound 40

Step 1: Synthesis of ethyl 2-(acetylthio)acetate (40-a)

In a three-necked flask (250 mL), the mixture of ethyl 2-bromoacetate(4.17 g, 0.025 mol) and potassium thioacetate (5.7 g, 0.05 mol) wasdissolved in dimethyl formamide (100 mL), and the resulting solution wasstirred at room temperature overnight. The reaction solution was addedwith water and ethyl acetate, organic layer was washed with saturatedbrine and dried over sodium sulfate, the solvent was removed by reducedpressure evaporation, thereby a brown oily substance was obtained anddirectly subject to the next step for reaction.

Step 2: Synthesis of ethyl2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)acetate (40-b)

In a single-necked flask (100 mL), 40-a (1.46 g, 9 mmol), anhydrouspotassium carbonate (1.24 g, 9 mmol) and 1-b (0.795 g, 3 mmol) wereadded to dimethyl formamide (20 mL), the mixture was stirred at roomtemperature for 1 hour, then heated to 130° C., and stirred with heatingfor 1 hour. After being cooled to room temperature, the reactionsolution was added with water and ethyl acetate, organic layer waswashed with saturated brine, dried over sodium sulfate, then the solventwas removed by reduced pressure evaporation, to give a crude brown oil,which was purified by column chromatography (petroleum ether/ethylacetate=1:1) to yield an oil.

H-NMR: (400 MHz, CDCl₃, ppm): δ 8.60 (d, J=5.6 Hz, 1H), 8.35-8.33 (m,2H), 7.99 (d, J=7.2 Hz, 1H), 7.75-7.72 (m, 1H), 7.58-7.55 (M, 2H), 7.49(d, J=7.2 Hz, 1H), 7.36-7.34 (m, 1H), 4.20-4.16 (m, 2H), 3.63 (s, 2H),1.26-1.24 (m, 3H).

Step 3: Synthesis ofdi(methyl-d3)-2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)aceticacid (40)

In a three-necked flask (50 mL), 40-b (110 mg, 0.3 mmol) dissolved intetrahydrofuran (1 mL) was slowly added dropwise into a suspension ofsodium hydride (60%, 28 mg, 0.69 mmol) in dimethyl formamide (1 mL) at0° C., after being stirred for 10 min, the mixture was further addeddropwise with a solution of iodomethane-d3 (136 mg, 0.94 mmol) indimethyl formamide (1 mL) at 0° C., then the mixture was stirred at roomtemperature overnight. After being quenched with water, the reactionsolution was adjusted to pH=4 with 1 N of hydrochloric acid, then thesolvent was removed by reduced pressure evaporation, and the remainingoil was purified by preparative HPLC to yield a light yellow solid.

LC-MS (ES, m/z): 355 [M+H]⁺; H-NMR: (400 MHz, CD₃OD, ppm): δ 8.52-8.50(m, 1H), 8.30-8.27 (m, 2H), 8.12-8.09 (m, 1H), 7.82-7.77 (m, 1H),7.68-7.60 (m, 2H), 7.55-7.48 (m, 2H).

Example 41: Synthesis of Compound 41

Step 1: Synthesis of ethyl2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)propanoate (41-a)

In a single-necked flask (50 mL), 1-b (264 mg, 1 mmol) and sodiumsulfide (234 mg, 3 mmol) were added to dimethyl formamide (10 mL), themixture was heated to 130° C. and reacted for 1 hour. After beingcooled, the mixture was further added with hydrous potassium carbonate(414 mg, 3 mmol) and ethyl 2-bromoacetate (716 mg, 4 mmol), then heatedto 130° C. and was allowed to further react for 1 hour. After beingcooled, the reaction solution was added with ethyl acetate (50 mL), andwashed with water (50 mL) and brine (50 mL). The organic phase wasdried, filtered, concentrated and purified by preparative silica gelplate (ethyl acetate/petroleum ether: 1/2) to yield a white solidproduct.

H-NMR: (400 MHz, d6-DMSO, ppm): δ 8.61 (dd, J=2.0 Hz, J=5.2 Hz, 1H),8.34 (d, J=5.6 Hz, 1H), 8.33-8.25 (m, 1H), 8.22 (d, J=8.4 Hz, 1H),7.85-7.84 (m, 1H), 7.66-7.63 (m, 1H), 7.63 (d, J=6.4 Hz, 1H), 7.58 (dd,J=3.2 Hz, J=7.6 Hz, 1H), 7.44-7.41 (m, 1H), 4.44-4.39 (m, 1H), 4.07-4.02(m, 2H), 1.32-1.30 (m, 3H), 1.10-1.06 (m, 3H).

Step 2: Synthesis of ethyl2-methyl-d3-2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio)propanoate(41-b)

In a three-necked flask (100 mL), under the protection of nitrogen,sodium hydride (16 mg, in oil (60%), 0.4 mmol) was added to dimethylformamide (5 mL), the mixture was then cooled to 0° C., and a solutionof 41-a (120 mg, 0.33 mmol) in tetrahydrofuran (2.5 mL) was addedthereto. The mixture was reacted at 0° C. for 0.5 hour, the reactionsolution was further added dropwise with a solution of iodomethane-d3(58mg, 0.4 mmol) in dimethyl formamide (1.5 mL), then heated to roomtemperature and reacted for another 16 hours. The reaction solution wasadded with ethyl acetate (50 mL), and washed with water (20 mL) andbrine (10 mL). The organic phase was dried, filtered, concentrated andpurified by preparative silica gel plate (ethyl acetate/petroleum ether:1/2) to yield a white solid product.

H-NMR: (400 MHz, d6-DMSO, ppm): δ 8.64 (d, J=5.2 Hz, 1H), 8.41 (s, 1H),8.28 (d, J=7.2 Hz, 1H), 8.22 (d, J=8.4 Hz, 1H), 7.83 (t, J=7.6 Hz, 1H),7.69 (t, J=7.6 Hz, 1H), 7.57 (d, J=7.2 Hz, 1H), 7.42-7.38 (m, 2H), 4.08(q, J=7.2 Hz, 2H), 1.37 (d, J=3.2 Hz, 3H), 1.10 (t, J=7.2 Hz, 3H).

Step 3: Synthesis of2-methyl-d3-2-((3-(4-cyanonaphthalen-1-yl)pyridin-4-yl)thio) propanoicacid (41)

In a single-necked flask (50 mL), 41-b (60 mg, 0.16 mmol) and lithiumhydroxide (41 mg, 0.97 mmol) were added to tetrahydrofuran/water (3 mL/1mL) and reacted at room temperature for 12 hours. The reaction solutionwas adjusted to pH=4 with dilute hydrochloric acid (1 M), added withethyl acetate (30 mL), and washed with brine (20 mL). The organic phasewas dried, filtered, concentrated and preparatively purified to yield awhite solid product.

LC-MS (ES, m/z): 352 [M−H]⁻; H-NMR: (400 MHz, d6-DMSO, ppm): δ 13.18(br, 1H), 8.61 (d, J=5.2 Hz, 1H), 8.36 (s, 1H), 8.26 (d, J=7.2 Hz, 1H),8.21 (d, J=8.4 Hz, 1H), 7.83 (t, J=7.6 Hz, 1H), 7.66 (t, J=7.6 Hz, 1H),7.57 (d, J=7.2 Hz, 1H), 77.51 (d, J=5.2 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H),1.37 (d, J=10.8 Hz, 3H).

Experimental Example 1: Evaluation of Bioactivity of Chemicals forInhibiting Absorption of Uric Acid Using URAT1 Cell Model

Human kidney embryonic cells HEK-293T were grown in a petri dish(diameter=10 cm) containing DMEM and 10% of bovine fetal serum culturesolution, and incubated in an 5% of carbon dioxide-containing incubatorat 37° C. Plasmids carrying human URAT1 were transfected to HEK-293Tcells using TransIT-293 (Mirus Bio LLC). After 72 hours, the petri dishcontaining HEK-293T cells transfected with URAT1 was removed from theincubator and the cells were inoculated on Poly-D-Lysine Coated 96-wellPlates at a density of 60,000 cells per well. After the cells on the96-well plates were grown overnight (at least 12 hours) in an incubatorat 37 degrees, these cells were gently rinsed 3 times with warm and nochloride ions-containing HBSS buffer (125 mM sodium gluconate, 4.8 mMpotassium gluconate, 1.3 mM calcium gluconate, 1.2 mM monopotassiumphosphate, 1.2 mM magnesium sulfate, 5.6 mM glucose, 25 mM HEPES, pH7.4). 50 microliter of HBSS buffer (not containing chloride ions)containing 0.2 microcurie of ¹⁴C-uric acid and compounds of the presentapplication or benzbromarone, and vector was added in each well, thenthe cell plates were put back to the incubator at 37 degrees. After 5min, the buffer was removed from cell wells, added with 100 microliterof ice-cold and no chloride ions-containing HBSS buffer to gently rinsecells within wells so as to stop them from absorbing ¹⁴C-uric acid, therinsing was repeated 3 times in the same manner. 150 microliter of celllysate (100 mM of NaOH) was added in each well. Cell plate was placed ona vibrating plate and vibrated for 10 min at a speed of 600 rpm suchthat the cells were completely lysed. The cell plate was put in acentrifuge and spun for 5 min at a speed of 1000 rpm, then 45 microliterof supernatant was sucked out from each well and transferred to 96-wellplate (Isoplate-96 Microplate from PerkinElmer). In the new 96-wellplate, 150 microliter of Ultima Gold XR scintillation solution was addedin each well. The 96-well plate was vibrated for 10 min at a speed of600 rpm on a vibrating plate. Finally, the 96-well plate was put in aMicroBeta Trilux Counter from PerkinElmer and was read, then IC₅₀ valueswere calculated, and the results are shown in Table 1 below. Wherein

TABLE 1 URAT1 IC₅₀ Compound No. Activity level 1 I 2 II 3 I 4 I 5 II 6III 7 II 8 III 9 III 10 III 11 I 12 II 13 II 14 II 15 II 16 I 17 I 18 I19 III 20 I 21 I 22 II 23 III 24 III 25 III 26 III 27 III 28 III 29 III30 III 31 III 32 III 33 II 34 II 35 II 36 III 37 III 38 III 39 III 40 I41 I benzbromarone II I represents that IC₅₀ value is in the range ofless than or equal to 100 nM; II represents that IC₅₀ value is in therange of less than or equal to 1000 nM and more than 100 nM; and IIIrepresents that IC₅₀ value is more than 1000 nM.

From the experimental data listed in the above Table 1, it can be seenthat, compared with existing compound benzbromarone, the compounds ofthe present invention have lower or similar IC₅₀ values, thereby it isdemonstrated that the compounds of the present invention have higheractivities of inhibiting the reabsorption of uric acid, and can be usedas novel and efficient drugs for reducing blood uric acid.

The examples and embodiments disclosed herein are merely for theillustrative purpose, and various amendments and modifications made by aperson skilled in the art will be included in the spirit and scope ofthe present application and are within the scope of the appended claims.

The invention claimed is:
 1. A compound selected from the groupconsisting of

or a pharmaceutically acceptable salt thereof.
 2. The compound of claim1, which is

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1, which is

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1, which is

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim1, which is

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim1, which is

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1, which is

or a pharmaceutically acceptable salt thereof.
 8. The compound of claim1, which is

or a pharmaceutically acceptable salt thereof.
 9. The compound of claim1, which is

or a pharmaceutically acceptable salt thereof.
 10. The compound of claim1, which is

or a pharmaceutically acceptable salt thereof.
 11. A pharmaceuticalcomposition comprising the carboxylic acid compound according to claim1, or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 12. A method of treating gout in a human, comprisingadministering to the human an effective amount of a compound selectedfrom the group consisting of

or a pharmaceutically acceptable salt thereof.
 13. The method of claim12, comprising administering to the human an effective amount ofcompound

or a pharmaceutically acceptable salt thereof.
 14. The method of claim12, comprising administering to the human an effective amount ofcompound

or a pharmaceutically acceptable salt thereof.
 15. The method of claim12, comprising administering to the human an effective amount ofcompound

or a pharmaceutically acceptable salt thereof.
 16. The method of claim12, comprising administering to the human an effective amount ofcompound

or a pharmaceutically acceptable salt thereof.
 17. The method of claim12, comprising administering to the human an effective amount ofcompound

or a pharmaceutically acceptable salt thereof.
 18. The method of claim12, comprising administering to the human an effective amount ofcompound

or a pharmaceutically acceptable salt thereof.
 19. The method of claim12, comprising administering to the human an effective amount ofcompound

or a pharmaceutically acceptable salt thereof.
 20. The method of claim12, comprising administering to the human an effective amount ofcompound

or a pharmaceutically acceptable salt thereof.
 21. The method of claim12, comprising administering to the human an effective amount ofcompound

or a pharmaceutically acceptable salt thereof.
 22. A method of reducingthe blood uric acid level in a human, comprising administering to thehuman an effective amount of a compound selected from the groupconsisting of

or a pharmaceutically acceptable salt thereof.
 23. A method of treatinghyperuricemia in a human, comprising administering to the human aneffective amount of a compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof.